FUNDAMENTALS of

Sleep Medicine
FUNDAMENTALS of

Sleep Medicine
Richard B. Berry, MD
Professor of Medicine
University of Florida, Gainesville
Medical Director
University of Florida and Shands Sleep Disorder Center
Gainesville, Florida
1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899

FUNDAMENTALS OF SLEEP MEDICINE ISBN: 978-1-4377-0326-9

Copyright 2012 by Saunders, an imprint of Elsevier Inc.

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Notices

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Library of Congress Cataloging-in-Publication Data

Berry, Richard B., 1947

Fundamentals of sleep medicine / Richard B. Berry.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-4377-0326-9 (pbk. : alk. paper) 1. Sleep disorders. 2. SleepPhysiological aspects. I. Title.
[DNLM: 1. Sleepphysiology. 2. Sleep Disorders. WL 108]
RC547.B47 2012
616.8498dc22 2011008073

Acquisitions Editor: Julie Goolsby

Developmental Editor: Jessica Pritchard
Publishing Services Manager: Pat Joiner-Myers
Project Manager: Marlene Weeks
Design Manager: Louis Forgione
Marketing Manager: Carla Holloway

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Printed in the United States of America www.elsevier.com | www.bookaid.org | www.sabre.org

Last digit is the print number: 9 8 7 6 5 4 3 2 1

This book is dedicated to my wife Cathy, my son David,
and my daughter Sarah.
They are my greatest joy.
 Preface

The goal of this book is to provide the reader with a core of fundamental knowledge about
sleep medicine and polysomnography. I have tried to write the book so that a person
without training in sleep medicine can start reading chapter one and progress until the end
of the book. With the publication of the International Classification of Sleep Disorders,
Second Edition, and the American Academy of Sleep Medicine scoring manual, there is a
need for an up-to-date text using current terminology and diagnostic criteria. A single text
cannot hope to cover all aspects of sleep medicine and sleep physiology. Therefore, I have
tried to focus on information that I feel is the most clinically useful. The field of sleep
medicine is changing so rapidly that any text is out-of-date before it is even published.
To this end, there will be an associated website to allow for updates, corrections, review
questions, illustrative case studies, and some video clips of parasomnias.
My inspiration for writing this book has come in part from the satisfaction and appre-
ciation that I received from writing the text Sleep Medicine Pearls. Sleep Medicine Pearls
had short fundamentals chapters mixed with cases and was heavy on graphics and illustra-
tive sleep tracings. I have tried to amplify the fundamentals sections to provide what I hope
is a concise and useful introduction to the entire spectrum of sleep disorders. In particular,
I have tried to cover aspects of the technology of sleep monitoring and interpreting sleep
studies that many new to the sleep field find difficult. The challenging but enjoyable experi-
ence of teaching sleep fellows and residents about sleep medicine has also prompted me to
write a book covering the fundamentals both to serve as an introductory text and to assist
those physicians actively taking care of sleep patients.

Richard B. Berry, MD

vii
viii Chapter 21

Acknowledgments

I would like to express my gratitude for the support and encouragement of the University
of Florida sleep physicians, including Dr. Abby Wagner, co-director of the University of
Florida Sleep Medicine Fellowship, Dr. Stephan Eisenschenk, and Dr. Craig Foster. It is a
pleasure to work with such a dedicated and talented group of individuals. I would also like
to thank Dr. Klark Turpen for her assistance in editing the book chapters. The patience and
assistance of the Elsevier editorial staff is also greatly appreciated. Jessica Pritchard helped
assemble the chapters and many figures. Dolores Meloni, Senior Acquisitions Editor, was
instrumental in developing the concept for the book and provided critical support in the
planning stages. Julie Goolsby, Associate Acquisitions Editor, provided encouragement
during the final stages of book preparation. I am also grateful for the patience and diligence
of Berta Steiner of Bermedica Production, Ltd. during the production process.

viii

Sleep Stages and Basic
Sleep Monitoring
Chapter Points
In the EEG or EOG derivation G1-G2, an upward deflection
in the tracing is noted if input G1 becomes negative with
respect to input G2 (negative upward polarity).
To differentiate whether alpha waves or sleep spindles
are present, change to a 10-second window and count
the individual deflections in one second (see Fig. 13).
K complexes and slow waves have the greatest
amplitude in frontal derivations. Sleep spindles and
saw-tooth waves have the greatest amplitude in
central derivations.
Alpha activity is any wave form with a frequency of 8
to 13 Hz. Alpha rhythm has a frequency of 8 to 13 Hz,
is most prominent in the occipital derivations, and is
enhanced by eye closure and attenuated by eye
opening.
The recommended EEG derivations are F4-M1, C4-M1,
and O2-M1.
The recommended EOG derivations are E1-M2 and
E2-M2. Both eye electrodes are referred to a common
mastoid electrode M2.
The front of the eye (cornea) is positive with respect to
the back of the eye (retina). If the eyes move toward
E1-M2 and away from E2-M2, this causes a downward
deflection in E1-M2 and an upward deflection in E2-M2.
In the recommended EOG derivations, eye movements
result in out-of-phase deflections. K complexes result
in in-phase deflections.
In stage R, the chin EMG amplitude is equal to or lower
than the lowest level in NREM sleep. The chin EMG
activity can reach the REM level during NREM sleep.
Transitions from NREM to stage R are not always
associated with a drop in chin activity. Chin EMG
activity is useful in differentiating stage R from stage W
with the eyes open (REMs present).
Sleep is divided into nonrapid eye movement (NREM)
and rapid eye movement (REM) sleep. Sleep staging is based
on electroencephalographic (EEG), electro-oculographic
(EOG), and submental (chin) electromyographic (EMG)
criteria. EOG (eye movement recording) and chin EMG
Chapter 1
recordings are used to detect REM sleep, which is character-
ized by REMs and reduced muscle tone. Since 1968, sleep
was usually staged according to A Manual of Standardized
Terminology, Techniques and Scoring System for Sleep Stages
of Human Subjects, edited by Rechtschaffen and Kales
(R&K).1 In the R&K scoring manual,1 NREM sleep was
divided into sleep stages 1, 2, 3, and 4. REM sleep was referred
to as stage REM. Sleep stage nomenclature has changed fol-
lowing the publication of the American Academy of Sleep
Medicine (AASM) Manual for the Scoring of Sleep and Associ-
ated Events (hereafter referred to as the AASM scoring
manual).2 The new nomenclature was introduced to denote
sleep stages defined by new criteria. The old and new nomen-
clatures are shown in Table 11. Stages 3 and 4 are combined
into stage N3.
Today, digital polysomnography (sleep recording) has
virtually replaced recording on paper. However, previously
sleep recording was performed with polygraphs using ink
writing pens with a paper speed of 10 mm/sec. At this paper
speed, a 30-cm page of paper contained 30 seconds of record-
ing. A sleep stage was identifed for each page (30 sec) termed
an epoch. The tradition of staging sleep in 30-second epochs
has been retained in the recent AASM scoring manual. The
sleep stage assigned to each epoch is the stage occupying the
majority of time within that epoch. Digital recording allows
display of data in one of several time windows (typically 5,
10, 30, 60, 90, 120, 240 sec). The 10-second window corre-
sponds to a paper speed of 30 mm/sec and is used for clinical
EEG monitoring. This time window also approximates elec-
trocardiographic (ECG) recording that was typically per-
formed using a paper speed of 25 mm/sec before the current
use of digital ECG recording.
EEG ELECTRODE PLACEMENT
Monitoring to detect the presence and stage of sleep requires
only a portion of the electrodes used in standard clinical
EEG recording (Table 12). The nomenclature for the EEG
electrodes follows the International 1020 system.3 The 10
20 refers to the fact that the electrodes are positioned at
either 10% or 20% of the distance between landmarks. The
major landmarks include the nasion (bridge of the nose),
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2 Chapter 1 Sleep Stages and Basic Sleep Monitoring

TABLE 11 TABLE 12
Sleep Stage Nomenclature Electroencephalographic Electrode Nomenclature
R&K AASM LEFT RIGHT MIDLINE
Wake Stage W Stage W Frontopolar Fp1 Fp2 Fpz
NREM Stage 1 Stage N1 Frontal F3 F4 Fz
Stage 2 Stage N2
Central C3 C4 Cz
Stage 3 Stage N3
Stage 4 Occipital O1 O2 Oz
REM Stage REM Stage R Mastoid M1 M2
AASM = American Academy of Sleep Medicine ; NREM = nonrapid eye
2

movement; R&K = Rechtschaffen and Kales A1; REM = rapid eye movement;
stages 3 and 4 are combined into stage N3.

FIGURE 11 Electrode positions using the 1020 Nasion

system.
10%

20% Fpz Fp2

Fp1

F3 Fz F4
20%

C3 Cz C4

M1 M2
20%

O1 O2

20% Oz

10%

Inion

inion (prominence at base of the occiput), and preauricular

points (Figs. 11 and 12). In the 1020 system, even-
numbered subscripts refer to the right side of the head and
odd-numbered subscripts to the left. Electrodes are named
for the part of the brain they are over. For example, Fp1 and
Fp2 are the left and right frontal pole electrodes, F3 and F4
are the left and right frontal electrodes, C3 and C4 are the
left and right central electrodes, and O1 and O2 are the left
and right occipital electrodes. Electrodes in the midline in
the frontopolar, frontal, central, and occipital regions are
named Fpz, Fz, Cz, and Oz, respectively. The position of the
electrode Cz is at the top of the head and is called the vertex.
The left and right mastoid electrodes in the new AASM
scoring manual nomenclature are named M1 and M2, respec-
tively. They were previously named A1 and A2. The nomen-
clature of EEG electrodes used for sleep monitoring is listed
in Table 12.
EEG Derivations
EEG signals are displayed as voltage differences between two
electrodes. The term derivation refers to a set of two elec-
trodes (and the voltage difference between the electrodes).
The term montage refers to a particular set of derivations.
In sleep monitoring, electrodes in the frontal, central, and
occipital electrodes are referenced against the opposite
mastoid electrode. The AASM scoring manual recommends
that all of the following electrodes be placed (F3, F4, C3, C4,
O1, O2, M1, and M2). The recommended derivations and the
alternative derivations are listed in Table 13. The backup
derivations are displayed if one of the electrodes in the rec-
ommended derivation fails. For example, if electrode F4 fails,
the derivation F3M2 is used. In digital recording, one can
easily display all six derivations if desired at the same time.
In the original R&K scoring manual, only central derivations
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 Chapter 1 Sleep Stages and Basic Sleep Monitoring 3

Cz FIGURE 12 Side, front, and back views

C3
of electroencephalographic (EEG) electrode
C4 F4 F3
Vertex placement using the 1020 system.
20% O2 O1
20% Oz
20%
F4
C4 20% M2
20% M1

10% 20%
10%
10% O2 10% Nasion

Inion Preauricular F4 F3
M2 Fpz
point
Fp2 Fp1
O1 Oz O2

Inion

TABLE 13 term derivation is used to describe the differential signal

Recommended Electroencephalographic
Derivations with Backup Derivations
RECOMMENDED DERIVATIONS2 BACKUP DERIVATIONS
F4-M1 F3-M2
C4-M1 C3-M2
O2-M1 O1-M2
were utilized. However, additional derivations allow better
visualization of the EEG patterns used to stage sleep.
Although the derivations cited previously are the most
widely used, the AASM scoring manual lists alternative
acceptable derivations (Table 14). The alternative deriva-
tions use the electrodes Fz, Cz, Oz, C4, and M1 with the backup
electrodes Fpz (to replace Fz), C3 (to replace Cz or C4), O1 (to
replace Oz), and M2 (to replace M1).
It is common to place additional electrodes beyond those
discussed in the AASM scoring manual to serve as a ground
electrode and common reference. In sleep monitoring, a
ground electrode is usually placed at or near Fpz and con-
nected to the ground (or iso-ground) input on the electrode
box. As discussed in Chapter 2, the ground is used to balance
the individual AC differential amplifiers. One electrode (or
two linked electrodes) is also placed to serve as a reference
for referential recording (see Chapter 2). The reference elec-
trode is commonly placed at or near Cz depending on which
EEG electrodes are to be recorded for sleep monitoring.
EEG Patterns
Recognition of certain characteristic EEG patterns is essen-
tial for sleep staging.16 EEG activity is recorded using a
differential AC amplifier such that the signal recorded is the
difference in voltage between two inputs (G1 and G2). By
EEG convention, if input G1 is negative with respect to G2,
this results in an upward deflection. As noted previously, the
between two inputs. For example, in the derivation C4-M1, a
change in the voltage between these electrodes results in an
upward deflection if C4 is negative with respect to M1. EEG
activity is described by frequency in cycles per second
(hertz = Hz), amplitude (microvolts [V]), and shape. The
classically described EEG frequency ranges are delta (<4 Hz),
theta (47 Hz), alpha (813 Hz), and beta (>13 Hz). Activity
that is faster results in narrower deflections and slower fre-
quency results in wider deflections. Sharp waves are narrow
waves of 70 to 200 msec duration and spikes have a shorter
duration of 20 to 70 msec.
Some of the characteristics of EEG patterns important for
sleep staging are listed in Tables 15 through 19. In addi-
tion to frequency, the region of highest activity (amplitude)
and the effects of maneuvers on the EEG activity are also
important. For example, one could use the term alpha activ-
ity to describe any EEG activity with a frequency in the
alpha range (813 Hz). However, alpha rhythm consists of
activity most prominent in occipital derivations that is atten-
uated by eye opening and increased by eye closure (Fig. 13).
An important part of biocalibrations (see Chapter 4) at the
start of sleep recording is to ask patients to close and then
open their eyes to document that they produce alpha rhythm.
Bursts of alpha waves can also occur during stage R typically
at a frequency 1 to 2 Hz slower than during wakefulness.
Sleep spindles79 are bursts of activity with a frequency
range of 11 to 16 Hz (usually 1214) with a duration of 0.5 sec
or greater (usually 0.51.5 sec). The term spindle is used
because the shape of sleep spindle burst is often like that of a
yarn spindle (see Fig. 13). If there is uncertainty about
whether activity is a burst of alpha activity or a sleep spindle,
one can display a 10-second window (see Fig. 13) and actu-
ally count the deflections (waves) per second. Sleep spindles
arise from thalamocortical oscillations. The reticular nucleus
of the thalamus is responsible for generating sleep spindles.
A K complex1,2,8,9 is a high-amplitude biphasic wave
composed of an initial negative sharp wave (deflection up)
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4 Chapter 1 Sleep Stages and Basic Sleep Monitoring

TABLE 14
Alternative Electroencephalographic Derivations with Backup Derivations
ALTERNATIVE DERIVATIONS FZ FAILS CZ FAILS OZ FAILS C4 OR M1 FAILS
Fz-Cz Fpz-Cz Fpz-C3 Fz-Cz Fz-Cz
Cz-Oz Cz-Oz C3-Oz Cz-O1 Cz-Oz
C4-M1 C4-M1 C4-M1 C4-M1 C3-M2

TABLE 15
Characteristics of Alpha Rhythm and Sleep Spindles
ALPHA RHYTHM SLEEP SPINDLES
813 Hz. 1116 Hz (classically 1214 Hz).
Most prominent over the occipital areas. Duration 0.5 sec (0.51.5 sec).
Activity increased by eye closure. Maximal over central areas.
Activity suppressed by eye opening. One of the defining characteristics of stage N2.
Predominate EEG activity in drowsy, eyes closed stage W. Thalamocortical oscillations (reticular thalamic
Common in REM sleep (12 Hz slower than during stage W or N1). nucleus).
Can occur with arousals (brief awakenings). Can be seen in stage N3 sleep.
10% of persons do not produce alpha rhythm with eye closure. Drug spindles (benzodiazepines) may be slightly faster.
EEG = electroencephalographic; REM = rapid eye movement.

TABLE 16
Characteristics of K Complex and Slow Wave Activity
K COMPLEX SLOW WAVE ACTIVITY
High amplitudebiphasic deflection. Frequency 0.52 Hz and > 75 V peak to peak in the
A well-delineated negative sharp wave (upward) followed by a frontal derivations.
positive (downward) slow wave. Used to define stage N3 sleep.
Stands out from the lower voltage background. Stage N2 < 20% SWA (<6 sec).
Duration 0.5 sec. Stage N3 20% SWA (6 sec).
Characteristic of stage N2 sleep. SWA is usually transmitted to eye derivations.
Maximal over frontal areas (frontal > central > occipital).
K complexassociated arousal requires arousal to start no more
than 1 second after K complex termination.
SWA = slow wave activity.

TABLE 17
Characteristics of Vertex Sharp and Saw-Tooth Waves
VERTEX SHARP WAVES SAW-TOOTH WAVES
Sharply contoured waves Trains of triangular waves, often serrated
Duration < 0.5 sec 26 Hz waves
Maximal over the central region (derivations containing C3, C4, Cz) Maximal in amplitude in central derivations
and distinguishable from the background activity (higher amplitude). Often, but not always, preceding a burst of REMs
Occurs in stage N1 often near transition to stage N2 Characteristic of stage R but not required for
scoring stage R
REMs = rapid eye movements.

followed by a slow wave (Fig. 14). A burst of spindle activity
is often superimposed on a K complex. A K complex stands
out from the lower voltage background. K complex activity
is greatest in frontal derivations (also central > occipital). A
K complex is said to be associated with an arousal if the
arousal commences no more than 1 second after the K
complex. An arousal during sleep stages N1, N2, and N3 is
scored if there is an abrupt shift of EEG frequency including
alpha, theta, and/or frequencies greater than 16 Hz (but not
spindles) that lasts at least 3 seconds, with at least 10 seconds
of stable sleep preceding the change. Arousals are discussed
in more detail in Chapter 3.
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 Chapter 1 Sleep Stages and Basic Sleep Monitoring 5

FIGURE 13 Alpha rhythm and sleep spindle activity as visualized

Alpha Sleep spindle in 30-second and 10-second windows.

30 second
window
(as viewed)

1 sec

10 second
window
(as viewed)

1 sec

TABLE 18
Summary of Important Wave Form Characteristics
ALPHA SLEEP VERTEX SLOW WAVE SAW-TOOTH
RHYTHM SPINDLE K COMPLEX SHARP WAVE ACTIVITY WAVES
Frequency (Hz) 813 1116 N/A N/A 0.52 26
Amplitude/ Oscillation Spindle- High amplitude Sharp wave High-amplitude Triangular,
shape shaped (usually > 100 V) broad wave serrated
oscillation Stands out against >75 V peak to
EEG background peak
Biphasic-negative
sharp wave
followed by positive
component
Duration Variable 0.5 >0.5 sec <500 msec 0.52 sec Variable
Location of Occipital Central Frontal Central Frontal Central
highest (vertex)
amplitude
Associated Stage W Stage N2 Stage N2 Stage N1 Stage N2 Stage R
sleep stages/ Stage N1 Stage N3 Stage N3 Stage N3
events Stage R
Arousals
EEG = electroencephalogram; N/A = not applicable.

TABLE 19 An example of a K complex associated with an arousal is

Electro-oculographic Derivations shown in Figure 15. Also note that the K complex is seen
RECOMMENDED ALTERNATE in the EOG derivations E1-M1 and E2-M2 as an in-phase
deflection.
E1-M2 E1-Fpz As noted previously, the frequency of delta activity is less
E2-M2 E2-Fpz than 4 Hz. EEG activity in this range produces relatively
wide duration deflections, often called delta or slow waves
(see Fig. 14). However, for sleep staging, the designation
slow wave activity (SWA)2 specifically refers to waves with
a frequency range of 0.5 to 2 Hz (2- to 0.5-sec duration) and
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6 Chapter 1 Sleep Stages and Basic Sleep Monitoring

100 V

1 sec
V

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin EMG

Alpha waves Sleep spindle K complex Vertex sharp Slow waves Saw-tooth waves
wave

FIGURE 14 Important EEG patterns for sleep staging. The grid lines are 1 second apart. V = position of the vertex sharp wave.

75 V

1 sec
F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin1-Chin2

FIGURE 15 A K complex associated with an arousal. An abrupt shift in EEG frequency immediately follows the K complex that lasts greater than 3 seconds. To be
considered associated with a K complex, an arousal must commence no later than 1 second after K complex termination.

a peak-to-peak amplitude of greater than 75 V in the
frontal derivations (see Fig. 14). SWA has the greatest
amplitude over frontal areas. In the R&K definitions, only
central derivations were utilized. Because slow wave ampli-
tude is higher over the frontal areas, a given epoch of EEG
activity would potentially have greater SWA (longer duration
meeting amplitude criteria) using the AASM scoring manual
definition2 (frontal derivations) compared with the R&K
definition (using central derivations).
Vertex sharp waves (see Fig. 14) are narrow-duration
waves (<500 msec according to the AASM scoring manual2)
prominent in derivations containing electrodes near the
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E2
ROC
1 cm
1 cm
1 cm 1 cm
LOC
E1 E2
Recommended Previous
vertex (Cz, C3, C4). They are often seen near the transition
between stage N1 and stage N2 sleep. Saw-tooth waves (see
Fig. 14) occur during REM sleep, although they are not
always present during this sleep stage. They are triangular
waves of 2 to 6 Hz of highest amplitude in the central deriva-
tions. The presence of saw-tooth waves is not required to
score stage R. However, the presence of saw-tooth waves is
very helpful when they occur.
EOG MONITORING FOR SLEEP
Recording of eye movements is possible because a potential
difference exists across the eyeball with the front/cornea
positive (+) and back/retina negative (). Eye movements are
detected by EOG recording of voltage changes associated
with eye movement.
The recommended EOG electrodes in the AASM scoring
manual2 are illustrated in Figure 16. E1 and E2 refer to the
left and right eye electrodes, respectively. Previously eye
electrodes were named right outer canthus (ROC) and left
outer canthus (LOC). For comparison, the positions of the
ROC and LOC electrodes are also shown. Please note that
E1 is placed below the LOC and E2 is placed above the ROC,
whereas LOC and ROC were placed lateral to the respective
outer canthus. Because E1 is below and E2 above the eyes,
vertical as well as horizontal movement can be detected.
Alternate eye electrode positions were also recommended
for use with alternate eye movement derivations (see
Fig. 16). The AASM scoring manual recommends the
EOG derivations E1-M2 and E2-M2 (see Table 18). Note
that both eye derivations use the right mastoid (M2) as the
reference electrode. Previous ROC and LOC derivations
varied between sleep centers, and these electrodes were ref-
erenced either to the same mastoid or to the opposite
mastoid. The AASM scoring manual also specified the alter-
native eye movement derivations (E1-Fpz and E2-Fpz). If these
eye movement derivations are used, both E1 and E2 are
below and lateral to the LOC and ROC, respectively (see
Fig. 16).
When the eyes move toward an electrode, a positive
voltage is recorded (Fig. 17). Recall that in EEG recording,
by polarity convention, if an eye electrode is negative com-
pared with the reference electrode, the signal has an upward
deflection. Thus, eye movement (cornea +) toward an elec-
trode referenced to another electrode further away from the
eyes results in a downward deflection.
Chapter 1 Sleep Stages and Basic Sleep Monitoring 7
Fpz FIGURE 16 Recommended, previous, and alternate
eye movement electrode positions. LOC = left outer
canthus; ROC = right outer canthus.
1 cm
1 cm
E1
Alternate
E2
Look Look
left right
   
E1
 
E1-M2
E2-M2
E1 positive to M2, E1 negative to M2,
deflection down deflection up
E2 negative to M2, E2 positive to M2,
deflection up deflection down
FIGURE 17 Schematic shows deflections in E1-M2 and E2-M2 from eye movements.
In the recommended EOG derivations, eye movements
result in out-of-phase deflections. This is because eye move-
ments are conjugate, and when both eyes move laterally or
vertically, they both move toward one EOG electrode and
away from the other EOG electrode. The polarity of the eye
electrodes determines the net voltage difference of the EOG
derivations because the electrodes are much closer to the
eyes than M2. The schematic in Figure 17 illustrates eye
movements and the resulting deflections (this assumes that
both eye derivation tracings have negative polarity upward
which is standard).
Note that when the alternate EOG derivations E1-Fpz and
E2-Fpz are used, both E1 and E2 are 1 cm below and 1 cm lateral
to the LOC and ROC, respectively. In this scheme, vertical
eye movements result in in-phase deflections and lateral eye
movements result in out-of-phase deflections (Fig. 18). The
advantages of the alternative EOG derivations are that verti-
cal deflections tend to produce larger deflections (blinks are
more prominent) and one can distinguish vertical (in-phase)
from horizontal (out-of-phase) eye movements. In addition,
it is easy to remember that downward eye movements result
in downward deflections in the eye derivations and upward
eye movements result in upward deflections. Alternatively,
the recommended eye derivations make it easier to recognize
artifacts or EEG activity transmitted to the eye derivations
because these cause in-phase deflections while eye move-
ments cause out-of-phase deflections (Fig. 19).
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8 Chapter 1 Sleep Stages and Basic Sleep Monitoring

Fpz Look Look Eye Movement Patterns

right left
Typical eye movement patterns (Table 110) include blinks,
   
slow eye movements (SEMs), REMs, and reading eye move-
E2 E1   ments (Fig. 110). SEMs are typical of eyes closed drowsy,
wakefulness, and stage N1 sleep. REMs are seen in eyes open
E1-Fpz
wakefulness or stage R sleep. SEMs typically disappear with
the onset of stage N2 sleep. However, patients on selective
E2-Fpz
serotonin reuptake inhibitors (SSRIs) can have eye move-
ments that are a mixture of slow and more rapid activity that
  persists into stage N2.10,11 This pattern is called Prozac eyes

TABLE 110
Fpz Look Look Eye Movements Pattern Definitions
up down Eye blinks: Conjugate vertical eye movements at a
    frequency of 0.52 Hz present in wakefulness with the
eyes open or closed.
E2 E1   Reading eye movements: Trains of conjugate eye
E1-Fpz movements consisting of a slow phase followed by a
rapid phase in the opposite direction as the subject reads.
Slow eye movements: Conjugate, fairly regular,
E2-Fpz sinusoidal eye movements with an initial deflection
lasting > 500 msec.
 
Rapid eye movements (REMs): Conjugate, irregular,
FIGURE 18 Schematic shows deflections in E1-Fpz and E2-Fpz due to horizontal and
sharply peaked eye movements with an initial deflection
vertical eye movements. Note that, using these derivations, vertical eye movements
usually lasting < 500 msec. Whereas rapid eye movements
result in in-phase deflections whereas lateral eye movements result in out-of-phase
are characteristic of stage R sleep, they may also be seen in
deflections. In addition, downward eye movements result in downward deflections.
wakefulness with eyes open (as patients look around the
room)
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007.

F4-M1

C4-M1

O2-M1

E1-M1

E2-M2

Chin EMG

K complex REM

FIGURE 19 Using the recommended electro-oculographic (EOG) derivations, the K complex results in deflections that are in phase and the rapid eye
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movement (REM) results in out-of-phase deflections. The vertical lines are 1 second apart. EMG = electromyography.
 Chapter 1 Sleep Stages and Basic Sleep Monitoring 9

100 V
1 sec

Slow eye E1-M2

movements
(SEMs) E2-M2

Rapid eye E1-M2

movements
(REMs) E2-M2

Reading eye
E1-M2
movements
E2-M2

E1-M2
Blinks
E2-M2

FIGURE 110 Eye movement patterns. The grid lines are 1 second apart.

but can occur with any of the SSRIs (see Chapter 4). Reading THREE ELECTRODES ARE RECOMMENDED
eye movements are due to a slow scan of the written page TO RECORD THE CHIN EMG
(left to right) followed by a rapid return to the left. This
results in a slowly increasing downward deflection in E2-M2
followed by a rapid upward deflection. In E1-M2, there is a
slow upward deflection followed by a rapid downward
deflection (see Fig. 110). Chin1

Chin (Submental) EMG Monitoring Chin2 Chin3

The monitoring of chin EMG activity is an essential element
only for identifying stage R (REM sleep). In stage R, the chin
EMG is relatively reduced: the amplitude is equal to or lower
than the lowest EMG amplitude in NREM sleep.
The placement of EMG electrodes recommended by the
AASM scoring manual is illustrated in Figure 111. The
scoring manual defines the positions of the electrodes but
does not assign them names.
For convenience, labels are assigned in Figure 111.
The standard chin derivation consists of either of the elec-
trodes below the mandible referred to the electrode above
the mandible. That is chin2chin1 or chin3chin1. The elec-
trode not used in the displayed derivation is placed as a
backup.
If the EMG derivation sensitivity (gain) is adjusted high
enough to show some activity in NREM sleep, a drop in
activity may be seen on transition to REM sleep. However,
the EMG can fall to the REM level before the onset of REM
sleep. Depending on the gain, a reduction in the EMG
amplitude from wakefulness to sleep and often a further
reduction on transition from stage N1 to stage N3 may be
seen. However, chin EMG activity is a requirement for
Electrode 1. Midline 1 cm above interior edge of mandible
Electrode 2. 2 cm below inferior edge of mandible and
2 cm right of the midline
Electrode 3. 2 cm below inferior edge of mandible and
2 cm left of the midline
Standard chin EMG derivations Chin2 - Chin1 or Chin3 - Chin1
FIGURE 111 Submental (chin) EMG electrode positions. The terms Chin1, Chin2, and
Chin3 are not specified in the American Academy of Sleep Medicine (AASM) scoring
manual but are added for convenience. The standard derivation is either of the electrodes
below the mandible referred to the electrode above the mandible.
identifying ONLY stage R. The reduction in the chin EMG
amplitude during REM sleep is a reflection of the general-
ized skeletal-muscle hypotonia present in this sleep stage. In
the tracings in Figure 112, there is a fall in chin EMG
amplitude (A) just before saw-tooth waves (B) and the REMs
(C) occur.
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10 Chapter 1 Sleep Stages and Basic Sleep Monitoring

B
F4-M1

C4-M1

O2-M1

E1-M2
C
E2-M2

Chin EMG
A

FIGURE 112 A 30-second tracing shows a reduction in the chin EMG on transition to stage R sleep (A). Note saw-tooth waves (B) and REMs (C).

CLINICAL REVIEW QUESTIONS: B. Minimum EEG amplitude peak to peak > 75 V in

frontal derivations, frequency 0.52 Hz
1. The standard EEG montage for sleep recording is F4-M1,
C4-M1, and O2-M1. If electrode C4 fails, which of the fol- C. Minimum EEG amplitude peak to peak > 75 V in
lowing montages should be used? frontal derivations, frequency < 4 Hz
A. F4-M1, C3-M2, O2-M1 D. Minimum EEG amplitude peak to peak > 50 V in
frontal derivations, frequency < 4 Hz
B. F4-M1, C3-M1, O2-M1
C. F3-M2, C3-M2, O1-M2 5. On right lateral gaze, which of the following deflections
D. F4-M2, C3-M2, O2-M2 are noted in the recommended EOG derivations?
A. E1-M2 Deflection up E2-M2 Deflection down
2. Alpha rhythm is characterized by which of the
B. E1-M2 Deflection down E2-M2 Deflection up
following?
C. E1-M2 Deflection up E2-M2 Deflection up
A. 813 Hz, attenuated by eye opening, most prominent
in occipital derivations D. E1-M2 Deflection down E2-M2 Deflection down
B. 1116 Hz, attenuated by eye closure, most prominent 6. Which of the following is true about SEMs (using the
in occipital derivations recommended eye derivations)?
C. 813 Hz, attenuated by eye opening, most prominent A. Can occur during stage W or N1, are sinusoidal out-
in frontal derivations of-phase eye movements.
D. 1116 Hz, attenuated by eye opening, most promi- B. Can occur during stage W only, are sinusoidal out-of-
nent in central derivations phase eye movements.
3. Sleep spindles are characterized by which of the C. Can occur during stage W or N1, are sinusoidal
following? in-phase movements.
A. 1214 Hz activity, most prominent in the occipital D. Can occur only during stage W only, are sinusoidal
areas out-of-phase movements.
B. 813 Hz, thalamocortical oscillations
C. 1116 Hz, most prominent in frontal derivations Answers
D. 1116 Hz, generated by the reticular nucleus of the 1. A. The alternate derivation for C4-M1 is C3-M2. It is
thalamus not necessary to change the other derivations. (See
FAQ for scoring manual V4. http://www.aasmnet.org/
4. SWA for sleep staging is characterized by which of the
FAQs.aspx?cid=29)
following?
A. Minimum EEG amplitude peak to peak > 75 V in 2. A. Alpha rhythm is 813 Hz, attenuated by eye opening,
central derivations, frequency 0.52 Hz most prominent in occipital derivations.
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 Chapter 1
3. D. Sleep spindles have a frequency of 1116 Hz and rep-
resent thalamocortical oscillations generated by the retic-
ular nucleus of the thalamus. Sleep spindles are most
prominent in central derivations.
4. B. SWA is characterized by a minimum amplitude peak
to peak of > 75 V in the frontal derivations with a fre-
quency of 0.5 to 2 Hz.
5. A. In the recommended derivations, eye movements
cause out-of-phase deflections. Because the cornea is
positive with respect to the retina, a rightward gaze results
in E2 being positive with respect to M2 (E2 is closer to the
cornea) and this results in a downward deflection. With
a rightward gaze, E1 is negative with respect to M2 (upward
deflection).
6. A. SEMs can occur during wake (eyes closed drowsy
wake) or stage N1 and are sinusoidal out-of-phase
movements.
REFERENCES
1. Rechtschaffen A, Kales A (eds): A Manual of Standardized
Terminology, Techniques and Scoring System for Sleep Stages
of Human Sleep. Los Angeles: Brain Information Service/Brain
Research Institute, UCLA, 1968.
2. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring
Sleep Stages and Basic Sleep Monitoring 11
of Sleep and Associated Events: Rules, Terminology and Tech-
nical Specifications, 1st ed. Westchester, IL: American Academy
of Sleep Medicine, 2007.
3. International Federation of Societies for Electroencephalogra-
phy and Clinical Neurophysiology: Ten twenty electrode
system. EEG Clin Neurophysiol 1958;10:371375.
4. Williams RL, Karacan I, Hursch CJ: Electroencephalography of
Human Sleep: Clinical Applications. New York: John Wiley &
Sons, 1974.
5. West P, Kryger MH: Sleep and respiration: terminology and
methodology. Clin Chest Med 1985;6:691712.
6. Caraskadon MA, Rechschaffen A: Monitoring and staging
human sleep. In Kryger MH, Roth T, Dement WC (eds): Prin-
ciples and Practice of Sleep Medicine. Philadelphia: Elsevier
Saunders, 2005, pp. 13591377.
7. DeGennaro L, Ferrara M: Sleep spindles: an overview. Sleep
Med Rev 2003;7:423440.
8. McCormick L, Nielsen T, Nicolas A, et al: Topographical dis-
tribution of spindles and K complexes in normal subjects. Sleep
1997;20:939941.
9. Silber MH, Ancoli-Israel S, Bonnet MH, et al: The visual
scoring of sleep in adults. J Clin Sleep Med 2007;15:121131.
10. Schenck CH, Mahowlad MW, Kim SW, et al. Prominent eye
movements during NREM sleep and REM sleep behavior dis-
order associated with fluoxetine treatment of obsessive-
compulsive disorder. Sleep 1992;15:226235.
11. Armitage R, Trivedi M, Rush AJ: Fluoxetine and oculomotor
activity during sleep in depressed patients. Neuropsychophar-
macology 1995;12:159165.
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DaneshGroup.com

The Technology of Sleep
Monitoring: Differential
Amplifiers, Digital
Polysomnography,
and Filters
Chapter Points
Common mode rejection of unwanted signals by a
differential AC amplifier depends on having low and
fairly equal electrode impedances. An electrode
impedance less than 5 K is desirable (<10 K
acceptable).
Digital PSG typically uses a combination of AC
referential, AC true bipolar, and DC recording.
In referential recording, each electrode is recorded
in comparison with a common reference electrode.
Any derivation (combination of differences between
electrodes) can be displayed by digital subtraction
[(C4-Ref ) (M1-Ref ) = C4-M1] during acquisition or later
during review of the study. If the reference electrode is
faulty, all channels will be affected.
Most digital AC amplifiers record with a wide bandwidth
(wide open), for example, a low-frequency filter of 0.03
and a high-frequency filter of 100 Hz. Each derivation is
then displayed after processing with the desired
low- and high-frequency digital filters. The recorded
data are not changed by the display filters. This allows
display with different filter settings if desired.
Digital recording requires appropriate sampling rates
by the A/D converter depending on the variable being
recorded. A suitable high-frequency filter must be
used to prevent aliasing distortion.
The resolution of the monitor is usually what limits the
possible resolution of the displayed data rather than
the sampling rate.
Chapter 2
In sleep monitoring (polysomnography [PSG]), electroen-
cephalographic (EEG), electro-oculographic (EOG), and
electromyographic (EMG) activity is recorded by differential
AC amplifiers that amplify the difference in voltage between
two inputs13 (Fig. 21). Each differential amplifier has two
inputs and a ground. By convention in EEG recording, if
input 1 (G1) is negative relative to input 2 (G2), the deflection
is upward (negative up polarity).
Signals common to both inputs are not amplified
(common mode rejection) (Fig. 22). Actually, each of the
inputs is recorded against the common ground and input 2
is inverted. This allows common signals to cancel each other
but differences between input 1 and input 2 to be amplified.
Use of differential amplifiers permits the recording of very
low voltage EEG signals that are superimposed upon larger
DC scalp voltage changes and 60-cycle interference from
nearby AC power lines. Common mode rejection depends
on the impedance at input 1 and 2 being relatively equal.
Otherwise, common signals will produce unequal voltages
at the two inputs. Making the intrinsic impedance of the
inputs much higher than the impedance of the electrodes
minimizes the effect of unequal electrode impedances.
However, a poorly conducting electrode (high impedance)
will typically result in a large amount of 60-Hz artifact (signal
contamination). The ground of each differential AC ampli-
fier is connected to the common patient ground (commonly,
an electrode placed on the forehead). This common ground
helps balance the inputs to all the differential amplifiers,
thereby improving common mode rejection. The use of
grounds in EEG recording is discussed at the end of the
chapter.
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13
14 Chapter 2 The Technology of Sleep Monitoring
It should be noted that a localized EEG transient (e.g.,
sharp wave) that is located midway between two electrodes
will produce an equal signal in both sides of the differential
AC amplifier that will cancel out (output approximately
zero). This cancellation effect will alter the overall EEG signal
amplitude less if electrodes are further apart. Thus, a greater
distance between two electrode inputs will increase the
amplitude of the recorded signal (less cancellation). This is
one reason the recommended EEG derivations use contra-
lateral mastoid references (C4-M1, not C4-M2).
REFERENTIAL AND BIPOLAR RECORDING
Most digital recording systems use a combintation of refer-
ential, true bipolar, and DC recording (Table 21).2 In true
bipolar recording, each amplifier records the difference
between two electrodes of interest (AB, CD). Before the
digital era, paper recording was performed using a selector
panel and dedicated individual differential amplifiers. Using
this approach, it is possible to change the electrodes (deriva-
tion) that are recorded with a given amplifier (Fig. 23).
However, changing the derivation once the signal is recorded
(changing from AB to AD) is not possible. Today, selector
panels are rarely used in digital sleep recording. However,
true bipolar recording is still used for inputs that one would
not desire to change in reviewfor example, the two inputs
of the thermal flow sensor, respiratory effort bands (thorax
IF G1 IS NEGATIVE TO G2,
DERIVATION G1-G2 THE DEFLECTION IS UPWARD

Differential amplifier 20 V
G1
G2
10 V
Ground
FIGURE 21 Differential amplifier. The difference between the two inputs is amplified
(for simplicity, the amplification factor = 1).
DIFFERENTIAL AMPLIFIER
80 V Common mode rejection
60 V
Input 1
Output 1
Input 2
FIGURE 22 Common mode rejection by a differential amplifier (for simplicity, the amplification factor = 1).
and abdomen), leg EMG inputs, and electrocardiographic
(ECG) inputs.
In referential recording, multiple electrodes are recorded
against a common electrical reference (often a single or two
linked electrodes placed near the vertex). A display of any
derivation using two referentially recorded electrodes is then
obtained by digital subtraction [(electrode A reference)
(electrode B reference) = electrode A electrode B] either
during live recording or during review (see Fig. 23). The
digital subtraction for display does NOT change the recorded
data. For example, if the sleep technologist failed to observe
that the electrode F4 went bad during the recording, the
reviewer can change the viewed frontal derivation to F3-M1
or F3-M2 (the recommended alternative) (Fig. 24). For this
reason, both F3 and F4 are recorded (against the reference
electrode) even though only F4-M1 may be displayed in the
default montage. Of note, if the reference electrode is faulty,
all referential signals are affected (Fig. 25). In Figure 25,
note that the true bipolar channels are not affected by a faulty
reference electrode. In most digital PSG systems, the EEG,
EOG, mastoid, and chin EMG electrodes are recorded refer-
entially (see Table 21). DC recording is used for nasal pres-
sure, pulse oximetry, and other DC signals such as those
TABLE 21
Types of Recording
Referential EEG: F4, F3, C4, C3, O2, O1, M1, M2
recording EOG: E1, E2, M1, M2
Chin1, Chin2, Chin3
Reference
30 V
True bipolar ECG, thermal flow, thorax and
(two inputs abdominal sensors, right and left
each) anterior tibial EMG
DC Nasal pressure, SpO2, positive airway
0 pressure device (flow, leak, pressure),
end-tidal or transcutaneous PCO2
ECG = electrocardiography; EEG = electroencephalography;
EMG = electromyography; EOG = electro-oculography; PCO2 = partial
pressure of carbon dioxide; SpO2 = pulse oximetry.
DETAILS
Input 1
Output
20 V
Ground 
0 
Ground
Input 2

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 Chapter 2 The Technology of Sleep Monitoring 15

BIPOLAR RECORDING REFERENTIAL RECORDING FIGURE 23 The difference between true bipolar
recording and referential recording. In referential
C4 C4-M1 C4
Amplifier 1
recording, each electrode is recorded against a common
C3 C3 reference. Specific derivations are then displayed by
C3-M2 Reference (Ref) digital subtraction (during acquisition or review).
M1 Amplifier 2 M1

M2 M2

Selector box
DISPLAY BIPOLAR VIEWS

C4  M1  (C4  Ref)  (M1  Ref)

C3  M2  (C3  Ref)  (M2  Ref)

F4-M1
F3-M1
C4-M1

O2-M1
E1-M2

E2-M2

Chin EMG

FIGURE 24 In the F4-M1, derivation 60-Hz artifact is present. The F4 electrode is at fault because other derivations containing M1 are not affected.
The displayed derivation is then changed to F3-M1, allowing an artifact-free frontal derivation to be viewed. Viewing a derivation using any two of the
referentially recorded electrodes is possible. The recommended derivation when the F4 electrode is faulty is actually F3-M2, but the use of F3-M1 is shown
for illustration. EMG = electromyography.

E1-M2

E2-M2

F4-M1

C4-M1

O2-M1

Chin1-Chin3

ECG
R, L legs

Airflow

Chest

Abdomen
SpO2
A B

FIGURE 25 A, The reference electrode is faulty. All referentially recorded electrodes show artifact. The true bipolar channels and DC
channels are not affected. In B, the reference electrode was repaired. SpO2 = pulse oximetry.
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16 Chapter 2 The Technology of Sleep Monitoring

1 sec Signal 4 Hz  4/sec TABLE 22

Recommended Sampling Rate for Various
Polysomnographic Signals
SAMPLING RATES DESIRABLE (HZ) MINIMAL (HZ)
Sampling rate 8/sec
EEG 500 200
EOG 500 200
8 samples/sec
EMG 500 200
Sampling rate 3/sec
ECG 500 200
Airflow 100 25
Oximetry 25 10
Nasal pressure 100 25
3 samples/sec
Esophageal pressure 100 25
FIGURE 26 A signal at 4 Hz is sampled at 8/sec with fair reproduction. However, with
sampling at 3/sec, the signal is distorted and a lower-frequency signal is introduced. Body position 1 1
Snoring 500 200
from the positive airway pressure device (flow, leak, Rib cage/abdominal 100 25
tidal volume, delivered pressure), end-tidal, or partial movements
pressure of carbon dioxide (PCO2) device (end-tidal or ECG = electrocardiography; EEG = electroencephalography;
transcutaneous). EMG = electromyography; EOG = electro-oculography.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
Sampling Rate Events: Rules, Terminology and Technical Specifications, 1st ed. Westchester,
IL: American Academy of Sleep Medicine, 2007.
Most digital recording systems use analog amplifiers that
produce a continuous signal output. The signal is then
sampled by an analog-to-digital (A/D) conversion board that A/D converter
converts the signal to a digital form that can be stored and Input at
12 bit (122  4096 bits)
manipulated by a computer. The sampling rate must be more head box
than twice the frequencies being recorded to avoid signal 000000000001
5 V ( 2.5 V) 000000000010
distortion (Nyquist theorem).1,2,4 If lower sampling rates are
4000 V

used, the signal can be very distorted and the addition of
frequencies lower than the original signal sampled may be
introduced (Fig. 26). For this reason, signals with a fre-
quency higher than half the sampling rate must be filtered
out because they can cause aliasing distortion.2,4,5 For
example, if the sampling rate is 200 samples/sec, the ampli-
fied signal must be processed by a high frequency filter with
a cutoff frequency of 100 Hz or lower before being sampled
(A/D converter). The required sampling rate depends on the
frequency of the signal to be recorded. Slower varying signals
require a lower sampling rate. In Table 22, the sampling
rates recommended by the American Academy of Sleep
Medicine (AASM) scoring manual6 are illustrated. Some
digital PSG systems have the ability to record different signals
at different sampling rates. Ultimately, the computer program
uses only a small portion of the data for the display because
monitor resolution (in pixels per displayed time duration) is
usually much less than the sampling rate.5
A/D conversion is also characterized by the dynamic
range (the range of voltages accepted by the A/D converter)
and the resolution. The dynamic range may be expressed as
the amplified or unamplified signal range. The resolution
depends on the A/D converter as well as the dynamic range.
A 12-bit DC converter produces 212 = 4096 digital values
(bits) or a 16-bit converter = 65,536 values across the dynamic
000000000011
 1250 000000000100
000000000101
000000000110
Etc,
Input at
A/D board
Resolution 0.97 V per bit
FIGURE 27 Dynamic range and resolution of an analog-to-digital (A/D) converter.
range. A typical A/D converter might have a dynamic range
for the amplified signal of 5 V (2.5 V). Commonly, a set
amplification is applied to all AC signals before A/D conver-
sion (e.g., a gain of 1250). If one assumes an amplification of
1250, then the dynamic range (peak to peak) of an A/D
converter with an amplified voltage range of 5 V expressed
as the unamplified signal would be approximately 4000 V
(4000 V 1250 = 5,000,000 V = 5.0 V). If a 12-bit A/D
converter is used, this would result in a resolution of 0.97 V/
bit (4000 V/4096 digital values) (Fig. 27).
Monitor Resolution
An important limitation on the accuracy of signal recording
and display is introduced by the fact that the monitor
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 Chapter 2 The Technology of Sleep Monitoring 17

Respiratory event
100%
95%

SpO2 90%
85%
80%
75%

Desaturation
Left
Right
Position Prone
Supine
Sitting

Wake
REM
Stage 1
2
3
Epoch
Time

FIGURE 28 An overview of the entire night of the recording shows respiratory events, pulse oximetry (SpO2), desaturation events, body position, and sleep stage
(hypnogram). REM = rapid eye movement.

resolution is usually much lower than the data sampling rate.
Because the sampling rate used for most digital systems is
200 samples/sec or higher, the resolution of the monitor is
often the limiting factor in the accuracy of signal display. The
minimum monitor resolution recommended by the AASM
scoring manual is 1600 1200. Assuming 1600 pixels hori-
zontally, the visual sampling rate for displays of a 30- or
10-second window of data corresponds to a sampling rate of
approximately 50 and 150 samples/sec if the entire monitor
display consists of waveforms. Then according to the Nyquist
theorem, frequencies of 25 or 75 Hz or greater would be
prone to aliasing. A monitor-induced aliasing distortion of
data can sometimes be noted if switching from a 30-second
to a 10-second view significantly changes the shape of the
activity being visualized.5
Time Window for Display
During traditional paper-ink recording for sleep, the paper
speed was 10 mm/sec, which produced 30-second pages (30-
cm-wide paper). A faster speed was used for clinical EEG
(30 mm/sec). However, such a fast paper speed would
produce a very large amount of paper for each sleep study.
In digital recording, one can choose various time windows
during either acquisition or review. A 30-second window
(equivalent to a paper speed of 10 mm/sec) is used for sleep
staging and for scoring arousals. Time windows of 60 to 240
seconds may be used to view and score respiratory events
and leg movements. Alternatively, viewing data in a
10-second window (equivalent to 30 mm/sec) is the usual
method for clinical EEG recording. This allows better visu-
alization of very brief events (sharp waves and spikes) and
interictal or epileptiform activity. The 10-second window
can also be useful for measuring the frequency of a group of
oscillations or viewing the ECG result. The traditional ECG
speed is 25 mm/sec, which is quite close to 30 mm/sec. Some
systems allow split screens with different time windows in
each screen. All digital sleep monitoring systems also provide
an all-night condensed view with graphs of the hypnogram
(representation of sleep stages), arterial oxygen saturation
(SpO2 tracing), continuous positive airway pressure (CPAP)
levels, respiratory events, and body position (Fig. 28). This
allows a useful overview of the entire recording. One can
usually select a time point (double click) on a given position
in the summary view and be taken to that time point in the
more detailed tracings.
FILTERS (LOW-FREQUENCY, HIGH-
FREQUENCY, AND NOTCH FILTERS)
Any signal of interest can be contaminated by unwanted
low- or high-frequency signals or 50- to 60-Hz artifact (from
nearby AC power lines). Filters allow these components to
be diminished. For example, a low-frequency filter (high-
pass filter) attenuates the amplitude of low-frequency signals.
A high-frequency filter (low-pass filter) attenuates the ampli-
tude of high-frequency signals.1 The amount of signal reduc-
tion due to a given analog or digital filter is given in decibels.
The amount of signal reduction in decibels (dB) is given by
the formula 20 log (voltage-out/voltage-in), where voltage-
out and voltage-in are the amplitude of the signal entering
and leaving the filter, respectively. A signal reduction of 30%
and 50% (voltage-out/voltage-in ratios of 0.7 and 0.5,
respectively) corresponds to 3 dB and 6 dB reductions. Dif-
ferent filter settings (e.g., 0.3, 1) are named by the cutoff
frequency, which is the frequency of the signal that is reduced
by 3 or 6 dB depending on the terminology and the type of
filter the manufacturer uses. Therefore, a filter setting of X
Hz means that the amplitude of a signal with a frequency
of X is diminished by 30% or 50% depending on whether the
3 dB or 6 dB cutoff frequency is used to name the filter.
Low-Frequency Filter
A 1-Hz low-frequency filter (3 dB) attenuates a 1-Hz signal
by 30% (or to 70% of the original signal). Similarly, a 6 dB
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18 Chapter 2 The Technology of Sleep Monitoring

filter would attenuate a 1-Hz signal by 50%. Signal strength
of frequencies below 1 Hz would be attenuated even more
(Figs. 29 and 210). It is important to realize that frequen-
cies slightly above the low-frequency filter setting of 1 Hz
will also be attenuated by a 1-Hz low-frequency filter,
although to a lesser degree. Figure 210 illustrates the effect
of various low-frequency filters (denoted by their 3 dB cutoff
frequency) on low-frequency signals. A range of possible
low-frequency filter settings (off, 0.01, 0.03, 0.1, 0.3, 1, 3, and
10) is commonly provided.
Sometimes low-frequency filter settings are specified as a
time constant rather than as a cutoff frequency (Fig. 211).
Traditional analog filters used resistance-capacitance (RC)
circuits. In RC circuits, an increase in step voltage produces
an abrupt increase in voltage across the resistor, then an
exponential fall in voltage to 1/e (0.37) of the maximum
voltage in one time constant (TC). In a simple, low-frequency
filter RC circuit, the frequency (fc) at which the output
voltage across the resistor is attenuated to 0.37% of the input
voltage is related to the TC by the formula fc = 1/(2/TC).
In RC circuits, the TC = RC, where R is the resistance and
C the capacitance of the circuit. Even if digital filters are
used, the relationship between the TC and the 3 dB fre-
quency is given by Equation 21:
TC = 1/(2 filter frequency ) Equation 21

FIGURE 29 A low-frequency filter setting LOW FILTER (HIGH PASS)

of 1 Hz attenuates a signal of 1 Hz by 50% (6 This assumes a 6 dB filter or filter setting = 1/2 amplitude
dB filter). Signals with lower frequencies are Filter settings Signals 1 to 10 Hz
attenuated more. Signals slightly above 1 Hz 0.1 0.3 1.0 1.0
100 100 are attenuated, but
are also attenuated (but < 50%). Note that
Percent amplitude

Percent amplitude
3 less than 50%
the horizonal axis uses a logarithmic scale and 75 75
Filter setting of 1
the vertical axis is linear. 50 10 50 reduces signal with
frequency of 1 Hz
25 25 by 50%
Filter settings 1.0
0 0 Lower frequency
0.1 0.2 0.5 1 2 5 10 0.1 0.2 0.5 1 2 5 10
attenuated more
Signal frequency Signal frequency than 50%

FIGURE 210 Effect of different low-frequency filter (LF)

settings (3 dB filter) given in hertz on slow wave
amplitude. Note that an LF 1 reduces a 1-Hz wave by about  1 Hz
30% (from 100 to 70 V). An LF 0.3 Hz reduced the 1-Hz
wave only slightly, whereas an LF 3 Hz essentially eliminated
1 Hz activity.
LF off 100

LF 0.3

LF 1 70

LF 3 100 V

1 second

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 Chapter 2 The Technology of Sleep Monitoring 19

FIGURE 211 The lower the low-frequency filter

C cutoff frequency (LF), the longer the time constant
Voltage (TC). Here, C is the capacitance and R is the resistance
Vin R 100 V in a traditional resistance-capacitance (RC) filter. Vin
= input voltage.
LF = 0.1 Hz TC = 1.6

Vin input
voltage LF = 0.3 Hz TC = 0.53

LF = 1 Hz TC = 0.16
Voltage 37%
across R
37% LF = 5 Hz TC = 0.03

TC
1 sec

30 Hz high filter FIGURE 212 The effects of a high-frequency filter. A 6 dB 30-Hz filter
0.3 Hz low filter Frequency slightly attenuates a 30-Hz signal by 50%. Signals less than 30 Hz are attenuated
lower than 30 Hz less (low pass). Signals with a frequency higher than 30 Hz are attenuated
100 attenuated slightly much more. The gray shows a frequency range that is attenuated less
Percent amplitude

75 than 0.70 by the combination of a 0.3-Hz low-frequency filter and a 30-Hz

30 Hz signal attenuated
high-frequency filter (HF). This is often referred to as the bandwidth
50 by 50% by a 6 dB 30 Hz HF
(or bandpass of the filters). Note that the horizontal axis of the plot
25 uses a logarithmic scale and the vertical axis is linear.
Frequency
0 higher than
0.1 0.2 0.5 1 2 5 10 50 100 200 30 Hz attenuated
0.3 30 even more
Signal frequency (Hz)

For example, a 0.3-Hz low-frequency filter has a TC of
approximately 0.53 second. Of note, the actual TC after a
step increase in voltage may vary depending on the high-
frequency filter setting as well. The lower the cutoff fre-
quency, the longer the time constant (see Fig. 211). If
amplifiers are calibrated by step (square wave) voltage
change, the actual TC can be noted from the time it takes
for the deflection to return to 0.37 of the maximum
deflection.
High-Frequency Filters
A 35-Hz high-frequency filter attenuates a signal of 35 Hz
by 50% (6 dB filter), and frequencies above 35 Hz would
be attenuated more. In addition, frequencies slightly below
the high-frequency filter setting will also be slightly attenu-
ated. Figure 212 illustrates the effects of a 6 dB 30 Hz
filter. A range of high-frequency filter settings is typically
provided (off, 3, 15, 35, 70, and 100 Hz). Note that using a
30-Hz high-frequency filter (see Fig. 212) significantly
attenuates 60-Hz signals. Therefore, the addition of a 60-Hz
notch filter adds little if a 30- to 35-Hz filter is already
being used.
Using the combination of a low-frequency and a high-
frequency filter, a range of frequencies is amplified. Alterna-
tively, if digital filters are applied to raw digital data, a range
of frequencies is displayed. The range of signal displayed or
amplified is called the bandwidth.
60-Hz or Notch Filters
Most amplifiers (digital PSG systems) provide optional notch
filters to significantly attenuate a narrow range of frequency
associated with power line signal contamination (e.g., 50 or
60 Hz). The notch filter can be added or removed. If the
notch filter is turned on, it is applied to the signal in addition
to the low-frequency and high-frequency filters. The routine
use of a notch filter is usually not recommended. The sudden
appearance of increased 60-Hz activity in a derivation is a
clue that one or more electrodes is faulty. However, as previ-
ously mentioned, use of a high-frequency filter of 35 Hz
(commonly used for EEG and EOG derivations) already
substantially attenuates a 60-Hz signal (much the same as
turning on the 60-Hz filter)
Turning on and off the 60-Hz (notch) filter can be useful
in determining the degree of signal contamination by 60-Hz
interference. If turning off the notch filter dramatically
increases signal amplitude, this suggests considerable 60-Hz
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20 Chapter 2 The Technology of Sleep Monitoring

FIGURE 213 If signal amplitude

increases significantly after the 60-Hz filter 60-Hz notch filter 60-Hz notch filter 60-Hz notch filter
is turned off, this is evidence that significant 100 V ON OFF OFF
HF 100 Hz HF 100 Hz HF 35 Hz
60-Hz activity is contaminating the signal.
Turning on and off the 60-Hz filter will have
less effect when the high-frequency filter
setting is 35 Hz because much of the 60-Hz
activity has already been filtered out. Chin1-Chin2

signal contamination (Fig. 213). One would expect switch- TABLE 23

ing on and off the 60-Hz filter to have more effect if a high-
frequency filter of 100 Hz was used (commonly used for
EMG derivations) compared with a high-frequency filter of
35 Hz (EEG and EOG derivations). For this reason, 60-Hz
contamination is most frequently visualized in the chin and
leg EMG derivations even if the 60-Hz filter is turned on.
Artifacts including 60-Hz artifact are discussed in more
detail in Chapter 4.
AMPLIFIER FILTER SETTINGS FOR
DIGITAL SLEEP RECORDING
Sleep recording with traditional dedicated bipolar AC ampli-
fiers used RC circuits (RC filters) as filters and the recorded
(on paper or computer) signal was filtered at the current
amplif ier settings. Today, most amplifiers used for digital
recording (referential and true bipolar) record signals wide
open, that is, with default low-frequency filter (0.030.1)
and a high-frequency filter setting usually at or less than half
the sampling rate (e.g., 100-Hz for a sampling rate of 200/
sec). Thus, raw signals are actually recorded over a wide
frequency range or bandwidth (between default low and
high frequencies) but are viewed (displayed) after applica-
tion of selected digital low-frequency and high-frequency
filters. The digital filters alter the displayed signal but NOT
the recorded data. This allows multiple choices of filters if
desired by the technologist or reviewer. The filter settings
recommended by the AASM scoring manual6,7 are shown in
Table 23. The filter settings are selected to include the fre-
quencies of interest in sleep monitoring. For example, to
detect slow waves and eye movements but avoid the effect of
scalp DC voltage changes (very low frequency), a low-
frequency filter of 0.3 Hz is selected. Setting the low-
frequency filter of the EEG or EOG channels higher would
reduce slow wave and eye movement amplitude. For EMG
and ECG channels, a low-frequency filter of 10-Hz is used,
because the relevant activity is of a much higher frequency.
For EEG and EOG monitoring, selection of a 35-Hz high-
frequency filter removes unwanted higher frequencies but
attenuates the characteristic EEG patterns such as sleep spin-
dles (1116 Hz) to a lesser degree. In contrast, the EMG
frequences of interest are much higher and a high-frequency
filter of 100 Hz is usually selected.
Recommended Filter Settings
LOW FREQUENCY HIGH FREQUENCY
EEG 0.3 Hz 35 Hz
EOG 0.3 Hz 35 Hz
EMG 10 Hz 100 Hz
ECG 0.3 Hz 70 Hz
Respiration 0.1 Hz 15 Hz
Snoring 10 Hz 100 Hz
ECG = electrocardiography; EEG = electroencephalography;
EMG = electromyography; EOG = electro-oculography.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
Events: Rules, Terminology and Technical Specifications, 1st ed. Westchester,
IL: American Academy of Sleep Medicine, 2007.
Clinical Example of the Effects of Filter Settings
As discussed in Chapter 7, monitoring nasal pressure pro-
vides a more accurate estimate of airflow than thermal
sensors. During upper airway narrowing, the nasal pressure
signal shows a flattening (flow plateau) during inspiration.
Some sleep centers record nasal pressure with an AC ampli-
fier instead of acquiring the signal in the DC mode. However,
a low-frequency filter setting of 0.03 or less (or a long TC) is
ideal to allow demonstration of a flow plateau in the nasal
pressure signal (Fig. 214). To accurately record or display a
very slowly varying signal, a sufficiently low cutoff frequency
must be used for the low filter.
If the nasal pressure signal is unfiltered, vibration during
snoring is often visible. However, the ability to see snoring
(high-frequency vibration) depends on the high-frequency
filter settings. Use of a fairly low high-frequency filter setting
will reduce high-frequency signals such as noted in the nasal
pressure tracing during snoring (Fig. 215). Ideally, one
would use a high-frequency filter setting of 70 to 100 Hz.
DIGITIAL PSG SYSTEM OVERVIEW
The typical digital PSG system includes a headbox in which
individual electrodes are attached to an amplifier. An
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 Chapter 2 The Technology of Sleep Monitoring 21

FIGURE 214 Effects of different low-frequency filter settings

Low filter on the nasal pressure signal. To visualize the plateau in the nasal
settings: pressure signal, either a DC recording or an AC recording with a
DC very small low-frequency filter setting is needed (either 0.01 or
0.03 is ideal).
0.01

0.03

0.1

0.3

Nasal pressure high filter 3 Hz

Nasal
pressure

Snore

Nasal pressure high filter off

Nasal
pressure

Snore

Snoring as vibration in nasal pressure signal

Effect of high (low pass) filter

FIGURE 215 Effect of a high-frequency filter of 3 Hz on a high-frequency signal (snoring).

accessory box for DC channel inputs or dedicated input jacks
on the amplifier are also usually available. The amplifier is
then connected to the A/D converter. Today, the A/D con-
verter is often contained within the amplifier that sits at the
patients bedside. The digitized signal can then be sent over
ethernet cables to the computer or sent in the wireless mode
to a computer, which then records the digital data. This
arrangement avoids the difficulties that occur when an
analog signal is sent over a long distance (60 Hz contamina-
tion or loss of signal strength). A schematic of a typical
system is shown in Figure 216. A typical PSG amplifier
often has a fixed gain and default low- and high-frequency
filter settings (e.g., 0.1 and 100 Hz). AC signals are recorded
over a wide frequency range (bandwidth). The A/D con-
verter samples the signal and raw digital data are stored in
the computer. After the raw data are digitized and stored,
extensive manipulation is possible to produce the desired
signal display. During acquisition and review, the computer
program performs digital subtraction to display the desired
derivations and processes the data with the selected digital
low-frequency and high-frequency filters. A display sensitiv-
ity is also chosen to determine the upper and lower limits
of data to be displayed in the channel width (digital gain).
The changes in the display (specific derivations, digital
filters, digital gain) do not change the raw data that are
recorded by the computer. The entire process is summarized
in Figure 216.
Montages for Digital Recording
Digital systems allow the user to specify a number of user-
defined display montages with the ability to select the
number of channels (traces) to be displayed, the derivations
for each channel, the order in which the desired derivations
are displayed (the inputs for each channel), as well as the
sensitivity (gain), low- and high-frequency filter settings,
notch filter on or off, and the color of each tracing. A sample
montage (Table 24) is displayed in Figure 217. Typically,
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22 Chapter 2 The Technology of Sleep Monitoring

Amplifier
Computer
Fixed
program Data
gain Raw
Electrode A/D display
LF 0.1 data Digital sensitivity
box converter
HF 100 stored Digital filters C4-M1
C4 -Ref (LF, HF)
M1 -Ref

FIGURE 216 Schematic of a digital polysomnography (PSG) system. In many systems, the A/D converter is within the same
unit housing the amplifier(s). Modern digital PSG systems usually perform a fixed amplification with default low (LF) and high
(HF) filters permitting a wide frequency range to be amplified. The digitized data are stored on media (hard drive in the
computer). The PSG software then scales the raw data, applies the selected low-frequency and high-frequency filters, and
provides a display (either during acquisition or at review).

TABLE 24
Montage 1: Diagnostic Adult
CHANNEL INPUT SENSITIVITY (P-P) LF HF NOTCH
(TRACING) TYPE INPUT 1 INPUT 2 V UNLESS DC (HZ) (HZ) FILTER
1 Ref F4 M1 150 0.3 35 Off
2 Ref C4 M1 150 0.3 35 Off
3 Ref O2 M1 150 0.3 35 Off
4 Ref F3 M2 150 0.3 35 Off
5 Ref C3 M2 150 0.3 35 Off
6 Ref O1 M2 150 0.3 35 Off
7 Ref E1 M2 150 0.3 35 Off
8 Ref E2 M2 150 0.3 35 Off
9 Ref Chin1 Chin2 150 10 100 Off
10 BP ECG1 ECG2 1500 0.3 70 Off
11 DC Nasal pressure N/A 1 to +1 V
DC 100 Off
*
12 BP NOTFinput 1 Input 2 750 0.1 15 Off
*
13 BP Snoreinput 1 Input 2 750 10 100 Off
*
14 BP Thoraxinput 2 Input 2 1500 0.1 15 Off
*
15 BP Abdomeninput 1 Input 2 1500 0.1 15 Off
16 DC SpO2 DC 01 V DC N/A Off
17 BP RATinput 1 Input 2 150 10 100 Off
18 BP LATinput 1 Input 2 150 10 100 Off
*The sensitivity settings for bipolar channels depend on the output range for a particular device.

Varies with transducer type.
BP = dedicated bipolar inputs (input-1, input-2); ECG = electrocardiography; HF = high frequency filter setting; LAT = left anterior tibial; LF = low frequency filter
setting; N/A = not applicable; NOTF = nasal-oral thermal flow sensor; P-P = peak to peak; RAT = right anterior tibial; Ref = referential input; SpO2 = pulse oximetry.

one montage is adapted for a diagnostic study and another
for a positive-pressure titration. During review or acquisi-
tion, each individual channel may be altered if so desired or
an entirely different montage may be displayed.
Channel Settings/Montages
Each channel (tracing) display can be changed by the viewer
with respect to the inputs, sensitivity (sometimes called
gain), low-frequency and high-frequency filters, channel
width, and inversion of signal. Default settings for each
channel can be specified, so they do not have to be individu-
ally set for each recording. Figure 217 illustrates typical
channel controls. Recall that changes in channel settings do
not change the recorded (and digitally stored) data.
In sleep recording using paper, the EEG was usually
recorded at a sensitivity of 50 V/cm in adults. In children,
a lower sensitivity (100 V/cm) was used because of the very
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 Chapter 2 The Technology of Sleep Monitoring 23

high amplitude EEG activity. The term gain rather than ultimate size of the channel width depends on the way the
sensitivity was also used. However, this implies an amplifica- computer program scales the signal for display. Some pro-
tion of signal. In digital recording, amplification actually grams have an option to allow signals either to overlap or to
occurs before the signal is digitized. The size of the display be cropped if they exceed the given channel width.
of a given signal is varied by the computer program that
scales the display based on the available channel width and Impedance Checking and Referential
the voltage limits or sensitivity. For example, if a channel
Display View
width of 100 pixels represents 100 V peak to peak, a signal
of 50-V peak to peak would vary between the 25th and the Traditionally, after electrodes were applied to the patients
75th pixel. The default digital displays for EEG often use 100 head, the impedance of each electrode was checked by plug-
or 150 V peak to peak per channel width (200 for children). ging the electrodes into an impedance box that allowed com-
Figure 218 shows two methods of adjusting the display parison of any electrode referred to the ground electrode or
(gain/voltage per division or peak-to-peak sensitivity). The a combination of all the other electrodes. Most digital
systems can measure impedance on line using a signal from
the amplifier. The values can then be stored with other digital
Channel 5 data for later review. The AASM scoring manual recom-
mends a maximum electrode impedance of 5 K (<10 K
Input 1 Input 2 Low freq filter High freq filter
is acceptable). Another useful method of looking at the
C4 M2 0.3 Hz 35 Hz
quality of each individual electrode is to display all of
the unfiltered referentially recorded electrode against the
Notch filter On Off common reference (rather than the digital subtraction of two
Trace width
100 Sensitivity referentially recorded electrodes). Figure 219 displays a ref-
erential view with all high-frequency filters set to 100 Hz.
100 V p-p Electrode impedance is also displayed. One can tell that F4,
Invert
Chin2, and Chin3 electrodes are faulty and should be
FIGURE 217 Example of typical controls for each display channel (tracing). Controls changed or fixed. As previously noted, if all tracings on the
allow selection of the derivation, low-frequency and high-frequency filters, notch filter referential view are bad, this suggests a problem with the
(on or off), and sensitivity. On most digital PSG systems, channel width and trace color reference electrode. However, a faulty reference electrode
can also be selected. p-p = peak to peak. does not affect the true bipolar channels (see Fig. 25).

1 second

One division

100 V/division
50 V/division

Channel width

100 V peak to peak 200 V peak to peak

FIGURE 218 Two methods of adjusting the sensitivity (digital gain) are shown. A 100-Hz peak-to-peak signal of 10 Hz is shown. The top panels
specify a voltage per division value. A larger channel width is needed to display a given signal if the actual division size remains constant when voltage per
division decreases. The bottom panel illustrates a method by which the peak-to-peak voltage of the entire channel width is specified. The actual
channel width will depend on the way the computer program scales the display.
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24 Chapter 2 The Technology of Sleep Monitoring

Impedance

O1-REF 6.4 K
O2-REF 6.3
C3-REF 5.6
C4-REF 2.5
E1-REF 3.5
E2-REF 4.4
M1-REF 4.8
M2-REF 4.3
Chin1-REF 3.8
Chin2-REF 19.2
Chin3-REF 10.3
F3-REF 6.7

F4-REF 30.2

FIGURE 219 A referential display with each electrode displayed against the common reference electrode. The electrode impedance is also displayed. One
can see that the Chin2, Chin3, and F4 electrodes should be replaced or repaired.

FIGURE 220 The three types of grounds AMPLIFIER SYSTEM

used in a modern PSG amplifier are illustrated
in a simplified schematic. The patient ground Isolated Non-isolated
section section
is separated from the earth ground by an
isolation device or isolated section of the Differential
amplifiers
amplifier. (Courtesy of Marc Paliotta, Grass F4
Technologies.) H = hot; N = neutral. Data
 Isolated power
C4 DC
 supply
Isolation barrier

Reference

Patient
ground Circuit
ground Power
Chassis
ground Earth ground NH

Video-Audio PSG
Today, most digital systems allow for the simultaneous
recording of video and audio signals. Ideally, the video
should be synchronized with the recorded EEG and other
signals. This will allow the reviewer to see patient movement
corresponding exactly to a given time point in the recorded
PSG signals. For example, one could note facial twitching
during a particular EEG pattern. Video PSG is an important
development and allows the reviewer to confirm the patient
position as well as document unusual behavior (e.g., para-
somnias) during the night. Video files are often quite large
and are usually compressed (e.g., MPEG4). The size of the
file will depend on the quality of the video (10 or 25 frames/
sec). Simultaneous audio is also usually available and this is
very useful for documenting teeth grinding (bruxism),
talking during parasomnias, snoring, and other behaviors
during the recording.
Grounds
The terminology is confusing with three different grounds
being used in modern PSG recording (Fig. 220). These
include
1. The patient ground (iso-ground input on the electrode
box). This neutral electrode is usually connected to the
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 Chapter 2 The Technology of Sleep Monitoring 25

forehead. It is used to balance the inputs of all the differ- C. Decreases the amplitude of a 0.1-Hz signal more than
ential amplifiers (essential for common mode rejection). a 0.3-Hz signal.
2. Chassis ground (container ground). Because a metal D. A and B.
chassis is rarely used today, this would be the amplifier E. A and C.
circuit ground (or the ground of the nonisolated portion
of the amplifier). 6. If a sampling rate of 400 samples/sec is used, what is the
3. Earth ground. In the three-wire power line (three-prong highest frequency cutoff for the high filter that can be
plug) AC input, the three wires are designated hot (H), used and still avoid significant aliasing distortion?
neutral (N), and earth ground. Most amplifiers use an A. 400 Hz.
isolated medical-grade power supply that outputs low- B. 200 Hz.
level DC voltage to power the amplifiers. C. 100 Hz.
In modern systems, the patient ground is never directly D. 50 Hz.
connected to the earth ground. A current-limiting device
7. Signals X, Y, and Z are recorded against a reference
or isolation device is always placed between the patient
(referential) and W1 and W2 are acquired by bipolar
ground and the earth ground. A common method is to use
recording (W1-W2) using digital PSG. Which of the
optical isolation in which the signal is transmitted by light
following is NOT true?
within a small element of the circuit. Figure 220 illustrates
one method in which part of the amplifier is isolated from A. The derivation X-Y can be displayed.
the chassis and earth grounds. B. The derivation W1-X can be displayed.
C. If all derivations containing X, Y, and Z show artifact,
CLINICAL REVIEW QUESTIONS the reference electrode is probably faulty.
1. What (low, high) filter settings are recommended for D. The filter settings of the displayed derivation W1-W2
PSG recording (display) of EEG and EOG derivations? can be changed.
A. 0.5, 70 Hz. 8. What is the minimum recommended sampling rate to
B. 0.3, 35 Hz. record the oximetry signal?
C. 0.5, 70 Hz. A. 50 samples/sec
D. 0.5, 35 Hz. B. 25 samples/sec.
C. 10 samples/sec.
2. What are the recommended (low, high) filter settings for
D. 100 samples/sec.
display of EMG?
A. 1 Hz, 70 Hz. 9. What is the recommended electrode impedance less
B. 0.3 Hz, 35 Hz. than?
C. 10 Hz, 100 Hz. A. 10 K.
D. 10 Hz, 70 Hz. B. 5 K.
C. 20 K.
3. What is the minimal recommended sampling rate for D. 1 K.
recording EEG, EOG, EMG, and ECG signals?
A. 100 samples/sec. 10. What are the recommended (low, high) filter settings for
display of the ECG?
B. 200 samples/sec.
A. 10, 100 Hz.
C. 400 samples/sec.
B. 0.3, 35 Hz.
D. 500 samples/sec.
C. 10, 70 Hz.
4. What is the minimal recommended sampling rate for D. 0.3, 70 Hz.
airflow, rib cage and abdominal movements, and NP?
11. Using a high filter of 35 Hz for the EEG and EOG display
A. 10 samples/sec. (recording) reduces 60-Hz activity in the displayed
B. 25 samples/sec. signal.
C. 100 samples/sec. A. True
D. 200 samples/sec. B. False
5. Which of the following is true about the effect of a low 12. What are the recommended (low, high) filter settings for
filter setting of 0.3 Hz? display of the thermal airflow or chest and abdominal
A. Has minimal effect on a 10-Hz signal. RIP signals?
B. Does not affect the amplitude of slow wave activity A. 0.3, 35 Hz.
(0.52 Hz). B. 0.1, 15 Hz.
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26 Chapter 2 The Technology of Sleep Monitoring
C. 0.3, 15 Hz.
D. 0.1, 35 Hz.
Answers
1. B.
2. C.
3. B.
4. B.
5. E. A low filter of X Hz has some effect on signals with
a slightly higher frequency than X. Therefore, a 0.3-Hz
filter does have some effect on a frequency range of 0.5
to 2 Hz. The lower a frequency signal is compared with
X Hz, the more the decrement in amplitude. A 0.3-Hz
filter decreases the amplitude of a 0.1-Hz signal more
than a 0.3-Hz signal.
6. B. 200 Hz. The Nyquist theorem states that the
minimum sampling frequency to record a signal of X Hz
is 2 X. Conversely, all frequencies greater than X are
undersampled if a sampling rate of 2 X is used and if
sampled can result in signal distortion. For this reason,
a high filter of X must be applied to the signal to dimin-
ish those frequencies before the total signal reaches the
A/D converter and is sampled.
7. B. True bipolar recording does not allow one part of the
derivation (W1, W2) to be displayed against another
electrode.
8. C. (10 samples/sec is the minimum recommended rate
but 25 Hz is desirable).
9. B. 5 K is recommended, <10 K or less is acceptable.
10. D. Although a high filter of 70 Hz is the official recom-
mendation, using a high filter setting of 100 Hz may
allow better visualization of pacer spikes.
11. True. A high filter with a cutoff setting of X reduces the
activity of frequency of signals higher than X. When
using a high-frequency filter of 35 Hz, turning on and off
the 60-Hz notch filter has less effect on the viewed signal.
12. B. Using a low filter of 0.1 instead of 0.3 allows more
accurate visualization of a slowly varying signal.
REFERENCES
1. Tyner FS, Knott JR, Brem Mayer W: Fundamentals of EEG Tech-
nology. New York: Raven, 1983.
2. Fisch BJ: Spehlmans EEG Primer. New York: Elsevier, 1991, pp.
3965.
3. Berry RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley
& Belfus, 2003, pp. 6769.
4. Epstein C: Digital EEG. Trouble in paradise? J Clin Neurophysiol
2006;23:190193.
5. Epstein CM: Aliasing in the visual EEG: a potential pitfall of video
display technology. Clin Neurophysiol 2003;114:19741976.
6. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring
of Sleep and Associated Events: Rules, Terminology and Techni-
cal Specifications, 1st ed. Westchester, IL: American Academy of
Sleep Medicine, 2007.
7. Silber MH, Ancoli-Israel S, Bonnet MH, et al: The visual scoring
of sleep in adults. J Clin Sleep Med 2007;15:121131.
DaneshGroup.com

Sleep Staging in Adults
Chapter Points
The AASM scoring manual uses new nomenclature for
wake and sleep (stages W, N1, N2, N3, and R). Stage N3
replaces stages 3 and 4 and stage R replaces stage
REM.
Sleep is scored in sequential 30-second epochs. If
more than one sleep stage occurs in an epoch, the
epoch is scored based on the sleep stage occupying
the majority of the epoch.
The 3-minute rule for stage N2 is no longer used.
The scoring of stage N3 is based on slow wave activity
in the frontal derivation.
If subjects do not generate alpha rhythm on eye
closure, the onset of stage N1 is based on the earliest
occurrence of slow eye movements, EEG activity in the
4 to 7 Hz range with slowing of the background
frequency by 1 Hz compared to wake, or vertex
sharp waves.
The AASM scoring manual provides specific rules for
scoring intervening epochs between epochs of
definite stage N2 and definite stage R. The scoring
manual does not provide rules for transitions between
stage W and stage R or between stage N1 and stage R.
Based on FAQ V7, begin scoring stage R when an
epoch of definite stage R is present (contains both low
EMG tone and REMs).
From 1968 to 2007, sleep was staged according to the
manual by Rechtschaffen and Kales (R&K).1,2 In the R&K
manual, only central derivations were used to stage sleep,
the term movement time was utilized to characterize
epochs in which the electroencephalographic (EEG) and
eye movement tracings are obscured by patient movement,
and there was a 3-minute rule for the continuation of stage
2 (now known as stage N2). The AASM Manual for the
Scoring of Sleep and Associated Events3,4 was published in
2007 (subsequently referred to as the AASM scoring
manual). This manual changed the rules of staging sleep
and made recommendations about the methods used to
monitor sleep.
Chapter 3
The AASM scoring manual uses new nomenclature (Table
31) for the sleep stages, uses frontal and occipital as well as
central EEG derivations, does not use the term movement
time, and has no 3-minute rule for stage N2 sleep. In addi-
tion, stages 3 and 4 are combined into stage N3. The succeed-
ing discussion follows the new rules with some minor
adaptations for brevity and clarity. Answers to questions
posed to the AASM Scoring Manual Steering Committee
and clarifications of the staging rules are posted in a fre-
quently asked questions (FAQs) document on the internet
(http://www.aasmnet.org/Resources/PDF/FAQsScoring
Manual.pdf). The definitions of the EEG and eye movement
patterns used for scoring are discussed in more detail in
Chapter 1.
SCORING BY EPOCHS
The AASM scoring manual continues the convention of
staging sleep in sequential 30-second epochs. Each epoch is
assigned a sleep stage. If two or more stages coexist during
a single epoch, the epoch is assigned the stage comprising
the greatest portion of the epoch.
Stage W (Wake)
During wakefulness, patients make the transition from full
alertness to the early stages of drowsiness. During eyes open
stage W (Fig. 31), the EEG consists of low-amplitude activ-
ity (chiefly beta and alpha frequencies) without the rhyth-
micity of alpha rhythm (813 Hz most prominent over
occipital derivations). Often, muscle artifact (high-frequency
activity) is also present in the EEG. Rapid eye movements
(REMs) and eye blinks (vertical movements 0.52 Hz) may
occur. The submental (chin) electromyogram (EMG) is
usually relatively increased compared with that during sleep.
The majority of individuals with eyes-closed stage W will
demonstrate alpha rhythm most prominent in the occipital
area. Slow eye movements (SEMs) may also be present and
the chin EMG activity is relatively high.
The rules for scoring stage W are listed in Table 32. In
subjects who generate alpha rhythm, stage W is scored when
more than 50% of the epoch contains alpha rhythm over the
occipital region (see Table 32, rule A). SEMs may or may
not be present during periods when alpha rhythm is present.
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28 Chapter 3 Sleep Staging in Adults

TABLE 31 TABLE 32
Comparison of R&K and the American Academy of Stage W Rules
Sleep Manual A. Score epochs as stage W when more than 50% of the
R&K* AASM SCORING MANUAL epoch has alpha rhythm over the occipital region.
1. EOG: Slow eye movements are characteristic of
Stage W Stage W eyes-closed stage W but are not required criteria for
Stages 1, 2, REM Stages N1, N2, R scoring stage W.
2. Chin EMG: The chin EMG amplitude is variable but is
Stages 3, 4 Stage N3
often higher than during sleep.
Central EEG derivations Frontal, central, and
B. Score epochs without visually discernible alpha
occipital derivations
rhythm (or portions of an epoch without alpha
3-minute rule for No time limit on stage N2 rhythm*) as stage W if any of the following are present:
continuation of stage 2 continuation 1. Eye blinks are present at a frequency of 0.52 Hz.
after an epoch with K 2. Reading eye movements are present.
complexes or sleep 3. Irregular conjugate REMs are present associated with
spindles normal or high chin muscle tone (in contrast, stage R
has low chin activity).
Movement arousal based on Arousal based on EEG (and
EMGan increase in the chin EMG for stage R) *Adaptation of AASM scoring manual stage W, rule B.
Notes:
EMG of any channel 1. Score stage W when the majority of an epoch has either alpha rhythm or
accompanied by a change eye movements consistent with wake as defined in B.
in pattern of any 2. Eye movement patterns (see Chapter 1).
additional channel A. Reading eye movements: trains of conjugate eye movements
consisting of a slow phase followed by a rapid phase in the opposite
Movement time when EEG No movement time direction as the subject reads.
and EOG obscured for Major body movement rules B. Blinks: conjugate vertical eye movements present in wakefulness with
eyes open or closed.
more than half the epoch C. REMs: conjugate irregular, sharply peaked eye movements with an
*Rechtschaffen A, Kales A (eds): A Manual of Standardized Terminology initial deflection lasting < 500 msec.
Techniques and Scoring System for Sleep Stages of Human Sleep. Los EMG = electromyogram; EOG = electro-oculogram; REMs = rapid eye
Angeles: Brain Information Service/Brain Research Institute, UCLA, 1968. movements.

Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Events: Rules, Terminology and Technical Specifications, 1st ed. Westchester, Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
IL: American Academy of Sleep Medicine, 2007. Westchester, IL: American Academy of Sleep Medicine, 2007.
EEG = electroencephalography; EMG = electromyography; EOG = electro-
oculography; REM = rapid eye movement.

100 V F -M
4 1

1 sec C4-M1

O2-M1
E1-M2

E2-M2

Chin EMG

Closed eyes Open eyes

FIGURE 31 Stage W. A 30-second epoch with eyes closed and then eyes open. More than 50% of the epoch has occipital alpha activity. EMG = electromyogram.

Epochs without visually discernible alpha rhythm (see Table
32, rule B) are scored as stage W if any of the following are
present: Eye blinks of a frequency of 0.5 to 2 Hz, reading eye
movements, or irregular conjugate REMs with normal or
high chin muscle tone. These eye movement patterns are
characteristic of stage W. The requirement of normal or high
chin EMG tone for REMs is because stage R (REM sleep) is
characterized by REMs and low muscle tone.
How should one score epochs that contain both portions
with alpha rhythm (but < 50% of the epoch) AND portions
with eye movements consistent with wake? The AASM
scoring manual did not specifically address this situation.
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 Chapter 3 Sleep Staging in Adults 29

However, one can modify stage W rule B to apply to the TABLE 33

portions of the epoch without alpha rhythm that contain eye
movements consistent with wake (see Table 32, rule B). If
the portions of the epoch containing alpha rhythm AND the
portions of the epoch considered to be wake due to eye
movements add up to more than 15 seconds (majority of the
epoch), then the epoch is scored as stage W.
Of note, approximately 10% of subjects do not generate
alpha rhythm on eye closure and a further 10% may generate
limited alpha rhythm. In these subjects, the occipital EEG
activity is similar during eye opening and eye closure. When
alpha rhythm is not generated with eye closure, the rules for
scoring stage W and stage N1 are somewhat different and
sleep onset is more difficult to define (Tables 33 and 34).
In patients who do not generate alpha rhythm, epochs satis-
fying rule B in Table 32 are scored as stage W. Otherwise,
epochs are scored as stage W if they do NOT meet criteria
for stages N1, N2, N3, or R. In contrast to patients generating
alpha rhythm, the presence of SEMs is a criterion for scoring
stage N1 in subjects who do not generate alpha rhythm (see
Table 34).
In Figure 31, a 30-second tracing shows the transition
from eyes-closed stage W to eyes-open stage W. Slightly
more than 50% of the epoch contains alpha activity. Alpha
activity is attenuated with eye opening and REMs are noted.
In Figure 32, portions of the epoch contain alpha rhythm
and other portions are considered stage W owing to the
presence of eye movements consistent with wakefulness
Stage N1 Rules
A. In subjects who generate alpha rhythm with eye
closure, score stage N1 if
1. EEG: Alpha rhythm is attenuated and replaced by
low-amplitude mixed-frequency (47 Hz) activity for
more than 50% of the epoch (<50% of the epoch has
alpha rhythm).
a. EEG: Vertex sharp waves may be present but are
not required for scoring stage N1.
2. EOG: Slow eye movements may be present in N1, but
these are not required for scoring N1.
3. Chin EMG: Variable amplitude, often lower than wake.
B. In subjects who do NOT generate alpha rhythm with eye
closure, score stage N1 commencing with the earliest of
any of the following phenomena:
1. The EEG shows 4- to 7-Hz activity with slowing of
background frequencies by 1 Hz or greater from those
of stage W.
2. Vertex sharp waves.
3. Slow eye movements.
Note: Because slow eye movements often commence before attenuation of
alpha rhythm, sleep latency may be slightly shorter for some individuals who
do not generate alpha rhythm than for those who do.
EEG = electroencephalogram; EMG = electromyogram;
EOG = electro-oculogram.
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007.

TABLE 34
Scoring Stage W and N1
EEG* EOG CHIN EMG
Alpha rhythm Stage W >50% of the epoch with alpha activity SEMs may be present Variable
on eye Eyes closed
closure Stage W Low-amplitude beta and alpha frequencies REMs Normal or high
Eyes open
Blinks Variable
Reading eye movements
Stage N1 >50% of epoch with alpha attenuation SEMs may be present Variable
and replacement with low-amplitude
mixed-frequency EEG
No alpha Stage W Low-amplitude beta and alpha frequencies REMs Normal or high
rhythm on
Eye blinks Variable
eye closure
Reading eye movements
SEMs absent
Stage N1 Vertex sharp wave Variable Variable
Slowing of 4 to 7 Hz, slowing of Variable Variable
frequency 1 Hz, compared to stage W
Low-amplitude beta and alpha frequencies SEMs appear Variable
Note: Bold text denotes essential features.
*The EEG is assumed not to contain sleep spindles or K complexes not associated with arousal.
EEG = electroencephalogram; EMG = electromyogram; EOG = electro-oculogram; REMs = rapid eye movements; SEMs = slow eye movements.
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30 Chapter 3 Sleep Staging in Adults

100 V F -M
4 1

C4-M1
O2-M1
E1-M2
E2-M2

Chin EMG

FIGURE 32 Stage W. A 30-second epoch containing rapid eye movements (REMs), high chin electromyographic (EMG) activity, and some alpha activity. The majority of the
epoch contains either alpha activity or eye movements consistent with wakefulness.

100 V
F4-M1
1 sec

C4-M1

O2-M1

E1-M2

E2-M2

Chin EMG

FIGURE 33 Stage W. A 30-second epoch is shown containing REMs, blinks, relatively high chin electromyographic (EMG) activity, and the absence of discernible alpha activity.

100 V
F4-M1
1 sec
C4-M1

O2-M1

E1-M2 SEM

E2-M2

Chin EMG

FIGURE 34 Stage W with the eyes closed. A 30-second epoch is shown. Note that alpha rhythm is more prominent in the occipital derivation and present for more than 50% of
the epoch. Slow eye movements (SEMs) are present in this epoch. Although characteristic, they are not a criterion for scoring stage W or N1 in patients producing alpha rhythm
with eye closure. The chin electromyography (EMG) has a low amplitude, but this is variable. In some patients, the chin EMG activity is higher in stage W than during sleep.

(see Table 32, stage W rule B). The majority of the epoch
contains either alpha rhythm or eye movements consistent
with wakefulness, and hence, the epoch is scored as stage W.
In Figure 33, the chin EMG activity is relatively high, REMs
and blinks are present, and there is no discernible alpha
activity. The epoch is scored as stage W using stage W rule
B (see Table 32). Figure 34 illustrates an example of
eyes-closed stage W. Here, greater than 50% of the epoch has
prominent alpha activity. SEMs are also present and the
EMG activity is relatively decreased. It should be noted that
SEMs can be seen during both eyes-closed stage W and stage
N1. If patients produce alpha rhythm with eye closure, SEMs
are not part of the criteria to score stage W (although they
are characteristic during eyes-closed stage W).
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 Chapter 3 Sleep Staging in Adults 31

Stage N1
Low-amplitude mixed-frequency (LAMF) activity is defined
as a low-amplitude EEG pattern with predominantly 4- to
7-Hz activity. Stage N1 is characterized by LAMF activity
and the absence of sleep spindles (SSs) and K complexes
(KCs) not associated with arousal. SEMs may occur (see
Table 33). At the transition from stage N1 to stage N2,
vertex sharp waves may appear. In patients who produce
alpha activity with eye closure (stage N1 rule A, see Table
33), the onset of stage N1 occurs when more than 50% of
the epoch is marked by alpha attenuation (alpha activity in
< 50% of the epoch) and replacement with LAMF EEG (Fig.
35). In individuals who do not produce alpha activity with
eye closure (Fig. 36), the start of stage N1 occurs at the
earliest occurrence of SEMs, a slowing of the EEG by 1 Hz
or more from that in stage W, or the presence of vertex sharp
waves (stage N1 rule B, see Table 33). Table 34 displays
the characteristics of stage W and stage N1 for patients who
do and do not produce alpha with eye closure. As noted in
the AASM scoring manual, because SEMs may occur before
alpha attenuation in subjects who have alpha activity with
eye closure, the sleep onset may be scored somewhat earlier
in patients who do not produce alpha activity with eye
closure.
Stage N2
Stage N2 is characterized by the presence of one or more
nonarousal KCs (i.e., KCs NOT associated with an arousal)
or one or more trains of SSs (Fig. 37). Arousal rules are
discussed later in this chapter. During epochs of stage N2,
eye movements have usually ceased and the chin EMG is
variable but usually at a level lower than that during wakeful-
ness. Recall that a KC is said to be associated with an arousal
(KC+Ar) if the arousal commences no more than 1 second
after the termination of the KC. Also note that the KC activ-
ity is seen in the recommended electro-oculographic (EOG)
derivations (E1-M2 and E2-M2) as in-phase deflections in
contrast to REMs (out-of-phase deflections). The rules for
scoring stage N2 are listed in Table 35 and summarized in
Table 36.
Start and Continuation of Stage N2
According to the stage N2 rules (see Table 35, rule A), begin
scoring stage N2 (see Fig. 37) when a KC (not associated
with an arousal) or an SS occurs in the first half of the
current epoch or the last half of the previous epoch. This
assumes that the epoch does not meet criteria for stage N3
(slow wave activity [SWA] present in 20% of the epoch,
i.e., 6 sec). Recall that SWA is defined as EEG activity of

100 V
F4-M1
1 sec
C4-M1
O2-M1
E1-M2
E2-M2

Chin1-Chin2

A
V
100 V
F4-M1
1 sec
C4-M1
O2-M1
E1-M2
E2-M2

Chin EMG

FIGURE 35 A, Stage N1. A 30-second epoch in which no sleep spindles or K complexes are noted in the electroencephalogram (EEG). Less than 50% of the epoch has alpha rhythm.
The EEG shows alpha attenuation and low-amplitude mixed-frequency (47 Hz) activity for more than 50% of the epoch. Slow eye movements are present but not required. The
chin electromyogram (EMG) is often lower than stage W. B, Stage N1. A vertex sharp wave (V) is noted. No sleep spindles or K complexes are seen in the EEG. The chin EMG is relatively
high in this example.
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32 Chapter 3 Sleep Staging in Adults

Eyes closed
100 V

1 sec F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
A

F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
B

F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
C

FIGURE 36 Thirty-second epochs. A, Biocalibration at the start of recording. The patient was asked to close his eyes. No alpha rhythm was generated. B and C, Consecutive
30-second epochs. B, An epoch of stage W with REMs and high chin electromyographic (EMG) activity. C, Slow eye movements are present and the EEG frequency slows. Therefore,
epoch C is scored as an epoch of stage N1 sleep. The chin EMG also falls in C, but this is not a criterion used for scoring stage N1 sleep.

75 V
F4-M1
1 sec SS
C4-M1
O2-M1
E1-M2
E2-M2
KC
Chin1-Chin2

FIGURE 37 Stage N2: A 30-second epoch with sleep spindles (SS) and K complexes (KC). The dark horizontal bars at the top denote the presence of slow wave activity (>75 V
peak to peak, 0.52.0 Hz). The total duration of slow wave activity is less than 6 seconds. The dotted lines in F4-M1 are 75 V apart.

0.5 to 2 Hz with greater than 75-V peak-to-peak amplitude
over the frontal areas. If the epoch in question contains 20%
or more SWA, then stage N3 is scored (Fig. 38). Most digital
polysomnography (PSG) systems allow display of amplitude
grid lines, and placing lines at 37.5 V + 37.5 V in F4-M1
or F3-M2 allows one to easily note 75-V peak-to-peak activ-
ity (see Figs. 37 and 38).
In the R&K scoring manual, stage 2 continued without
additional SSs or KCs for a maximum of 3 minutes (the
3-min rule). If no new KCs or SSs were noted for more than
3 minutes, the epochs following the epoch with the last KC
or SS (during the 3-min period) were scored as stage 1 and
subsequent epochs were scored as N1 (unless there was new
evidence for another sleep stage). In the AASM scoring
manual, there is no such time limitation. Stage N2 continues
until there is a reason to score an end of a period of stage N2
sleep (see Table 35, rule B). If an arousal occurs, a major
body movement (MBM) followed by SEMs (signaling a
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 Chapter 3 Sleep Staging in Adults 33

TABLE 35
Stage N2 Rules*
A. RULE DEFINING THE START OF N2 SLEEP
1. EEG: Begin scoring stage N2 (in the absence of evidence of N3, SWA < 6 sec) if one or both of the following occur during
the first half of the current epoch or the last half of the previous epoch:
a. One or more K complexes unassociated with arousals or
b. One or more trains of sleep spindles.
2. EEG: If the only K complexes present are associated with arousal, continue to score stage N1.
3. EOG: Usually no eye movements, slow eye movements have ended.
4. Chin EMG: Variable, usually less than wake.
Note: SWA = EEG activity 0.52 Hz with > 75 V peak-to-peak amplitude in the frontal areas. If SWA > 20% of the epoch (6 sec), score stage N3.

B. RULE DEFINING THE CONTINUATION OF STAGE N2 SLEEP

1. Continue to score epochs with low-amplitude mixed-frequency EEG activity without K complexes or sleep spindles as
stage N2 if they are preceded by an epoch containing:
a. K complexes unassociated with arousals or
b. Sleep spindles.
C. RULE DEFINING THE END OF A PERIOD OF STAGE N2 SLEEP
1. End stage N2 sleep when one of the following events occurs:
a. Transition to stage W, stage N3, or stage R.
b. An arousal (change to stage N1 until a K complex unassociated with an arousal or a sleep spindle occurs).
c. A major body movement followed by slow eye movements and low-amplitude mixed-frequency EEG without
nonarousal associated K complexes or sleep spindles then score epochs after the major body movement as N1.
i. If no slow eye movements follow the major body movement, score the epoch as stage N2.
ii. The epoch containing the body movement is scored using criteria for major body movements.
*See later rules for arousal (see Table 315) and major body movements (see Table 314).
EEG = electroencephalography; EMG = electromyography; EOG = electro-oculography; SWA = slow wave activity.
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
Events: Rules, Terminology and Technical Specifications, 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.

TABLE 36
Summary of Scoring Stage N2
START N2 CONTINUE N2 STOP N2
KC or SS in first half of EEG with LAMF without KC or SS. Transition to stage W, N3, or R.
current epoch or last half IF the epoch (or a group of epochs) is preceded Arousal.
of the previous epoch. by an epoch with a nonarousal KC or SS. Major body movement followed by an SEM.
EEG = electroencephalogram; KC = K complex not associated with arousal; LAMF = low-amplitude mixed-frequency; SEM = slow eye movement; SS = sleep spindle.

75 V F4-M1
1 sec
C4-M1
O2-M1

E1-M2
E2-M2
Chin EMG

FIGURE 38 Stage N3 sleep (30-sec epoch). The dotted lines in F4-M1 are 75 V apart. The grid lines are 1 second apart. Slow wave activity is present in all 30 seconds of the epoch
(Table 37).
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34 Chapter 3 Sleep Staging in Adults

transition to stage N1), or the epoch meets criteria for stages
W, N3, or R, then stage N2 ends (see Table 35, rule C.1.a).
Figure 39 is a schematic illustrating the start of stage N2
sleep. Epoch 101 has a KC not associated with an arousal in
the first half of the epoch and is scored stage N2. In epoch
201, the KC begins in the second half of the epoch so stage
N2 begins in epoch 202. Stage N2 continues in epochs 102
and 103 and 202 and 203 even though no SSs or KCs occur.
Note that a KC+Ar is NOT evidence that stage N2 has begun
(Fig. 310, epoch 101).
TABLE 37
Stage N3 Rules
A. Score stage N3 when 20% or more of an epoch consists
of SWA, irrespective of age (20% of 30-sec epoch = 6 sec).
1. EEG: SWA 20% of the epoch (6 sec), sleep spindles
may be present in stage N3.
2. EOG: Eye movements are not typically seen during
stage N3 sleep.
3. EMG: In stage N3, the chin EMG is of variable
amplitude, often lower than in stage N2 sleep and
sometimes as low as in stage R sleep.
Definition: SWA = EEG activity 0.52 Hz with peak-to-peak amplitude > 75 V
measured over the frontal areas.
Note: SWA may be seen in the EOG derivations.
EEG = electroencephalogram; EMG = electromyogram;
EOG = electro-oculogram; SWA = slow wave activity.
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007.
End of Stage N2: Effects of Arousals
Stage N2 ends following an arousal (see Table 35, rule
C.1.b). Unless there is a transition to another sleep stage,
stage N1 is scored until there is evidence for resumption
of stage N2 (see Table 35, rule A). Note if an arousal inter-
rupts stage N2 in the second half of the epoch, the epoch is
still scored as stage N2 because the majority of the epoch is
stage N2. The effects of an arousal are illustrated in Figure
310. An arousal occurs in epoch 201. Because the arousal
occurs in the last half of the epoch, the current epoch remains
as stage N2 but the next epoch is scored as stage N1. Stage N2
resumes only when there is evidence of a KC not associated
with an arousal or SS (using rules for the start of stage N2).
End of Stage N2: Effect of MBM
A major body movement (MBM) is defined as movement
and muscle artifact obscuring the EEG for more than half an
epoch to the extent that the sleep stage cannot be deter-
mined. If stage N2 is interrupted by an MBM followed by an
SEM and LAMF, stage N1 is scored until there is evidence
to restart stage N2 (SS or KC not associated with an arousal)
(see Table 35, rule C.1.c). If the MBM is NOT followed by
an SEM, stage N2 does not end unless there is a transition
to stage W, N3, or R (see Table 35, rule C.1.c). In Figure
311, an MBM interrupts stage N2 sleep. In Figure 311A,
the MBM is not followed by SEMs and stage N2 continues.
The epoch with the MBM is scored using rules discussed
later. In Figure 311B, the MBM is followed by an SEM and
LAMF EEG activity and the epoch after the MBM is scored
as stage N1. Stage N2 resumes only when there is new

Epoch Epoch
100 101 102 103 200 201 202 203
K complex Low amplitude Low amplitude K complex
mixed frequency mixed frequency
F4-M1 F4-M1

C4-M1 C4-M1

O2-M1 O2-M1

E1-M2 E1-M2

E2-M2 E2-M2

Chin EMG Chin EMG

Stage N1 Stage N2 Stage N2 Stage N2 Stage N1 Stage N1 Stage N2 Stage N2

FIGURE 39 Schematic examples of the start and continuation of stage N2 sleep (stage N2 rules A and B; see Table 35). Score stage
N2 in epoch 101 as a nonarousalK complex is noted in the first half of the epoch. Stage N2 continues in epochs 102 and 103. In
epoch 201, the K complex occurs in the last half of the epoch, so stage N2 begins in epoch 202. The schematics assume the EEG activity
is low-voltage mixed-frequency unless otherwise depicted.
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 Chapter 3 Sleep Staging in Adults 35

Epoch Epoch
100 101 102 103 200 201 202 203
K complex
associated with arousal
Arousal

F4-M1 F4-M1

C4-M1 C4-M1

O2-M1 O2-M1

E1-M2 E1-M2

E2-M2 E2-M2

Chin EMG Chin EMG

Stage N1 Stage N1 Stage N1 Stage N2 Stage N2 Stage N2 Stage N1 Stage N2

FIGURE 310 Schematics illustrating the effects of a K complex associated with an arousal (epoch 101) (stage N2 rule A; see Table
35) and an arousal interrupting stage N2 sleep (stage N2 rule C.1.b; see Table 35). Epoch 202 is scored as stage N1.

Epoch Epoch Epoch

200 201 202 203 300 301 302 303 400 401 402
Low amplitude Low amplitude
K complex mixed frequency K complex K complex K complex mixed frequency

F4-M1 F4-M1 F4-M1

No alpha No alpha
Alpha
C4-M1 C4-M1 C4-M1

O2-M1 O2-M1 O2-M1

E1-M2 E1-M2 E1-M2

SEM
E2-M2 E2-M2 E2-M2

Chin EMG Chin EMG Chin EMG

Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage Stage
N2 N2 N2 N2 N2 N1 N1 N2 N2 W N1
Major body movement
A B C

FIGURE 311 A major body movement (MBM) interrupts stage N2 (stage N2, rule C.1.c). A, If the epoch containing the MBM has no alpha and there are no slow eye movements
(SEMs) in the subsequent epoch, stage N2 continues (epochs 202 and 203). B, If SEMs and low-amplitude mixed-frequency (LAMF) activity follow the MBM, a transition to stage
N1 is scored (epoch 302). C, If the MBM epoch contains alpha, the epoch is scored as stage W (see MBM rules in Table 35, rule C.1.c). In this case, stage N2 ends. The next epoch
of sleep without K complexes or sleep spindles is scored as stage N1.

evidence for this sleep stage (a KC not associated with an
arousal or an SS).
As discussed in a subsequent section on MBM scoring, if
any alpha is present in the epoch (even < 15 sec) containing
the MBM, then the epoch is scored as stage W. In this case,
the period of stage N2 ends (see Fig. 311C). If the epoch
preceding or following an MBM is scored as stage W, the
MBM epoch is scored as stage W. Otherwise, the MBM
epoch is scored based on the stage of the following epoch
(see Major Body Movements, later) (see Tables 313 and
314, later in this chapter).
Stage N3
In stage N3, the amount of SWA (SWA = EEG activity
of 0.52 Hz and a peak-to-peak amplitude of > 75 V
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36 Chapter 3 Sleep Staging in Adults
SW
100 V
F4-M1
1 sec C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 312 Stage R. A 30-second epoch of definite (unambiguous) rapid eye movement (REM) sleep. Saw-tooth waves (SW) are not required to score stage R but are helpful.
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 313 Stage R. A 30-second epoch containing transient muscle activity (TMA) in the chin EMG.
measured over the frontal areas) is equal to or greater than
20% of an epoch (6 sec). The SWA is also noted in the EOG
derivations but SEM or REMs are not present. The chin EMG
is variable but typically less than during wake. The amount
of stage N3 decreases in adult men but not women as age
increases. This is primarily due to a decrease in EEG ampli-
tude (in the 0.22 Hz range) that occurs in men with aging.
In Figure 37, SWA is denoted by dark horizontal bars at the
top of the tracing and the total duration of SWA is less than
6 seconds. If SWA is 6 seconds, the epoch would be scored
as stage N3. Figure 38 shows an epoch of stage N3. Nearly
all of the epoch meets SWA amplitude criteria.
Stage R
The EEG activity in stage R resembles that of stage N1 and
generally contains LAMF activity. However, alpha activity in
stage R is usually more prominent than in stage N1 and
usually has a frequency 1 to 2 Hz lower than during wakeful-
ness. The three components of stage R are (1) a low-amplitude
EEG without KCs or SSs, (2) REMs, and (3) low chin EMG
tone (activity). In the AASM scoring manual, low EMG tone
is defined as baseline EMG activity in the chin derivation no
higher than in any other sleep stage and usually at the lowest
level of the entire recording. These three components of stage
R may not all start or stop at the same time. In addition,
REMs are episodic and not all epochs of stage R have REMs.
Therefore, special rules are needed for the start, continuation,
and end of stage R as well as transitions from N2 to REM
sleep. Saw-tooth waves are often present in epochs of stage
R. They are 2- to 6-Hz triangular waves maximal over central
regions (Fig. 312). During burst of REMs, transient muscle
activity (TMA) is also often seen during stage R. TMA is
characterized by short irregular bursts of EMG activity
(<0.25 sec) in the chin derivations superimposed on low chin
activity (Fig. 313). Saw-tooth waves and TMA are NOT part
of the criteria for scoring stage R but are strongly supportive
that stage R is present. TMA may also occur in leg EMG
derivations often associated with bursts of REMs.
Definite REM Sleep (REM Rule A)
When epochs have all three characteristics of REM sleep
(Table 38, REM rule A), they are considered definite or
unambiguous epochs of REM sleep (see Fig. 312). The EEG
has low amplitude mixed frequency activity, REMs are
present, and chin EMG tone is low. However, contiguous
epochs (before or after definite epochs of REM sleep) that
lack REMs but have a REM-like EEG with no sleep spin-
dles or K complexes and low chin EMG activity are often
scored as stage R, if they meet criteria specified in the stage
R rules.
Stage REM typically follows epochs of stages N2 and, less
commonly, stage W or stage N1. The AASM scoring manual
lists rules for transition from stage N2 to stage R (see later).
The manual does not address transitions from stage W or
stage N1 to stage R. However, based on FAQ V7, stage R is
not scored following stage W or N1 until an epoch of definite
REM sleep is noted.
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TABLE 38
Stage R Rule A (Definite REM Sleep)
A. Score stage R sleep in epochs with all the following
phenomena (definite or unequivocal REM epochs):
a. Low-amplitude mixed-frequency EEG.
b. Low chin EMG tone (the baseline EMG activity in the
chin derivation is no higher than in any other sleep
stage and usually at the lowest level of the entire
recording).
c. REMs.
Notes:
1. Low chin EMG tone: The baseline EMG activity in the chin derivation is no
higher than in any other sleep stage and usually at the lowest level of the
entire recording.
2. REMs: Conjugate, irregular, sharply peaked eye movements with an initial
deflection usually lasting < 500 msec.
3. Definite stage R (unequivocal stage R) = EEG without spindles or K
complexes, REMs, low chin EMG activity (at REM level).
EEG = electroencephalogram; EMG = electromyogram; REM = rapid eye
movement.
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007.
Continuation of REM Sleep (REM Rule B)
REM rule B (Table 39) is illustrated in the schematic in
Figure 314. Epochs following epochs of definite stage R
continue to be scored as stage R even if no REMs are present
so long as the chin EMG stays at the REM level and there
are no KCs or SSs in the EEG. If the EMG increases above
the REM level for a majority of an epoch, stage R can no
longer be scored (see Fig. 314, epoch 202).
End of REM Sleep
Stage R ends (see Table 39, REM rules C.l.a to C.1.e) when
there is a transition to stage W or N3, the chin EMG increases
above the REM level for the majority of the epoch, an arousal
occurs followed by an SEM(s), an MBM occurs followed by
SEMs, or there is a transition to stage N2 of sleep (appear-
ance of KCs or SSs in the first half of the epoch).
End of REM Sleep: Transition to Stage W or N3
Stage R ends if there is a transition to stage W or stage N3
(stage R rule C.1.a). Transitions from stage R to stage N3 are
very rare. However, awakenings out of REM sleep are
common. Patients may often return to sleep and subse-
quently reenter stage R. The AASM scoring manual does not
directly address transitions from stage W to stage R. However,
based on FAQ V7 concerning transition from N1 to stage R
(see later section), one would not resume scoring stage R
unless an epoch of definite stage R was present (REM-like
EEG, REMs, and low chin EMG tone) even if a preceding
epoch had a chin EMG at the REM level. In Figure 315,
stage R ends when there is a transition to stage W. Stage R
begins when there is an epoch of definite stage R (epoch
304).
Chapter 3 Sleep Staging in Adults 37
TABLE 39
Continuation and End of Stage R (REM Rules
B and C)
B. Continuation of stage R: Continue to score stage R
sleep, even in the absence of REMs, for epochs following
one or more epochs of stage R as defined above
(unequivocal REM epochs), if
a. EEG continues to show low-amplitude mixed-frequency
activity without K complexes or sleep spindles.
b. Chin EMG: Tone remains low (at REM level).
C. End of stage R.
1. Stop scoring stage R sleep when one or more of the
following occur:
a. There is a transition to stage W or N3.
b. An increase in chin EMG tone above the level of
stage R is seen and criteria for stage N1 are met.
c. An arousal occurs followed by low-amplitude
mixed-frequency EEG and slow eye movements
(score as stage N1; if no slow eye movements and
chin EMG tone remains low, continue to score as
stage R).
d. A major body movement followed by slow eye
movements and low-amplitude mixed-frequency
EEG without nonarousal-associated K complexes or
sleep spindles (score the epoch after the major
body movement as stage N1; if no slow eye
movements and the EMG tone remains low,
continue to score as stage R; the epoch containing
the body movement is scored using major body
movement criteria).
e. One or more nonarousal-associated K complexes
or sleep spindles are present in the first half of the
epoch in the absence of REMs, even if chin EMG
tone remains low (score as stage N2).
EEG = electroencephalogram; EMG = electromyogram; REM = rapid eye
movement.
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007.
End of REM Sleep: Increase in Chin EMG Activity
Stage R ends if there is an increase in chin EMG tone above
the level of stage R and criteria for stage N1 are met (see
Table 39, rule C.1.b). In Figure 314, epoch 102 remains
stage R because the chin EMG does not increase until the
second half of the epoch. In epoch 202, the chin EMG
increases above the REM level and criteria for stage N1 are
met (see Table 39, stage R rule C.1.b).
End of REM Sleep: Arousal Followed by LAMF EEG
and SEMs
Stage REM ends if there is an arousal followed by LAMF
EEG and SEMs (score as stage N1). If the arousal is not fol-
lowed by SEMs and the chin EMG remains low, stage R
continues (see Table 39, REM rule C.1.c). In Figure 316A,
an arousal interrupts stage R, but the epoch following the
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38 Chapter 3 Sleep Staging in Adults

Epoch Epoch
100 101 102 103 200 201 202 203
Low amplitude K complex Low amplitude
mixed frequency mixed frequency
F4-M1 F4-M1

C4-M1 C4-M1

O2-M1 O2-M1

REM REM

E1-M2 E1-M2

E2-M2 E2-M2

Chin EMG Chin EMG

Stage R Stage R Stage R Stage N2 Stage R Stage R Stage N1 Stage N2

FIGURE 314 Schematics illustrate the continuation of REM sleep (stage R, rule B; see Table 39). Epochs 100 and 200 are definite
(unequivocal) stage R. Subsequent epochs are scored as stage R even in the absence of REMs if the EEG does not have K complexes or sleep
spindles and the chin EMG remains at the REM level. Epoch 102 is scored as stage R because the chin EMG activity remains low for the majority
of the epoch. The arrows show the time when the chin EMG is no longer at the REM level.

FIGURE 315 An epoch of stage W interrupts stage R. Stage R

starts again when a definite epoch of stage R is noted (epoch 204). Epoch
EMG = electromyography; REM = rapid eye movement; SEM = slow 200 201 202 203 204
eye movement. (See frequently asked question [FAQ] V7 at Low amplitude
http://www.aasmnet.org/Resources/PDF/FAQsScoringManual.pdf). mixed frequency
F4-M1
Alpha
C4-M1

O2-M1
REM SEM
E1-M2

E2-M2

Chin EMG

Stage Stage Stage Stage Stage

R W N1 N1 R

Major body movement

arousal continues to be scored as stage R (even in the absence
of REMs) because the chin EMG remains at the REM level
for the majority of the epoch and there is no evidence of
stage N1 (no SEM following the arousal) or stage N2 (EEG
with KCs or SSs). However, in Figure 316B, the arousal is
followed by SEMs and stage N1 is scored.
End of REM Sleep: MBM Followed by LAMF EEG
and SEMs
When REM sleep is interrupted by an MBM followed by
SEMs and LAMF EEG without nonarousal-associated KCs
or SSs, the epoch after the MBM is scored as stage N1 (see
Table 39, REM rule C.1.d). If the MBM is not followed by
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 Chapter 3 Sleep Staging in Adults 39

FIGURE 316 Stage R is interrupted by an

Epoch Epoch arousal (stage R, rule C.1.c; see Table 39).
100 101 102 103 200 201 202 203 The EEG in the following epoch has no sleep
K complex K complex spindles or K complexes and the chin EMG
Arousal Arousal
returns quickly to the stage R level. A, No
F4-M1 F4-M1
slow eye movement (SEM) follows the
arousal, and because the chin EMG returns
C4-M1 C4-M1 quickly to the REM level, stage R continues.
B, An SEM follows the arousal and stage N1
is scored (epoch 202). REM = rapid eye
O2-M1 O2-M1 movement.
REM REM
SEM
E1-M2 E1-M2

E2-M2 E2-M2

Chin EMG Chin EMG

Stage R Stage R Stage R Stage N2 Stage R Stage R Stage N1 Stage N2

A B

FIGURE 317 Rapid eye movement (REM)

Epoch Epoch sleep interrupted by a major body movement
200 201 202 203 300 301 302 303 (MBM) (stage R, rule C.1.d; see Table 39).
Low amplitude Low amplitude
mixed frequency mixed frequency

F4-M1 F4-M1
No alpha No alpha
C4-M1 C4-M1

O2-M1 O2-M1
REM REM

E1-M2 E1-M2
SEM

E2-M2 E2-M2
Low amplitude
mixed frequency
Chin EMG Chin EMG

Stage Stage Stage Stage Stage Stage Stage Stage

R R R R R N1 N1 N1
A B

SEMs and the EMG tone remains low, stage R continues. The
epoch containing the MBM is scored using MBM criteria
(see Table 314). In Figure 317, stage R is interrupted by an
MBM. In Figure 317A, the MBM epoch is not scored as
wake owing to the absence of alpha activity (see MBM rules)
and is not followed by an SEM. Therefore, stage R continues
and the MBM epoch is scored based on the following epoch
(stage R). In Figure 317B, an SEM follows the MBM,
signifying a change in sleep state. Stage R ends and the epoch
is scored as stage N1. In this case, the MBM epoch (see MBM
rules) is scored based on the following epoch (stage N1).
End of REM Sleep: Appearance of Nonarousal KCs or
SSs in the EEG
If stage R is interrupted by one or more nonarousal-associated
KCs or SSs that are present in the first half of the epoch in
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40 Chapter 3 Sleep Staging in Adults

Epoch Epoch
100 101 102 103 200 201 202 203
Low amplitude K complex Low amplitude K complex
mixed frequency mixed frequency
F4-M1 F4-M1

C4-M1 C4-M1

O2-M1 O2-M1
REM REM

E1-M2 E1-M2

E2-M2 E2-M2

Chin EMG Chin EMG

Stage Stage Stage Stage Stage Stage Stage Stage

R R R N2 R R R N2

FIGURE 318 Schematic illustrates the end of stage R owing to transition to stage N2 (stage R, rule C.1.e; see Table 39). In epoch
202, the K complex appears only in the second half and the chin EMG is at the rapid eye movement (REM) level. Therefore, the next
epoch is scored as stage N2.

the absence of REMs is scored as stage N2 (even if chin EMG
tone remains low) (see Table 39, REM rule C.1.e). In Figure
318A, stage R ends when a KC not associated with an
arousal is present in the first half of the epoch. The start of
N2 follows the N2 rule (KC/SS located in the first half of
the epoch 103). Epoch 103 is scored as stage N2. In contrast,
in Figure 318B, because the KC occurs in the second half
of the epoch 202 and the chin EMG remains at the REM
level, epoch 202 remains stage R but epoch 203 is scored as
stage N2.
TRANSITIONS BETWEEN DEFINITE
STAGE N2 AND STAGE R
Intervening epochs between that last epoch of definite stage
N2 (KC or SS in the first half of the epoch or last half of the
previous epoch) and definite stage R are scored according to
REM rule D (Table 310).
If epoch(s) preceding and contiguous with an epoch of
definite stage R has (have) a chin EMG at the REM level and
no KCs or SSs in the EEG, such an epoch is (epochs are)
scored as stage R even in the absence of REMs (Fig. 319)
using stage R rule D1 (see Table 310). In Figure 319, epoch
101 is scored as stage R because the chin EMG is at the REM
level for the majority of the epoch. Epoch 201 cannot be
scored as stage R because the chin EMG is above the REM
level for the majority of the epoch and is scored as N2.
If the chin EMG falls to the REM level in the first part of
the epoch but a KC or SS occurs in the epoch contiguous
TABLE 310
Transitions between Stage N2 and Stage R
(REM Rule D)
D. Score epochs of transition between stage N2 and stage
R as follows:
1. In epochs between definite N2 and definite stage R,
score stage R (even in the absence of REMs) if:
a. There is a distinct drop in the chin EMG to the
REM level in the first half of the epoch.
b. There is absence of nonarousal-associated K
complexes and sleep spindles.
2. In epochs between definite stage N2 and definite
stage R, score stage N2 if all the following are met:
a. There is a distinct drop in the chin EMG to the
REM level in the first half of the epoch.
b. There is the presence of nonarousal-associated K
complexes and sleep spindles.
c. Absence of REMs.
3. In epochs between definite N2 and definite stage R,
score stage R even in the absence of REMs if:
a. There is a low chin EMG activity (at the REM
level) for the entire epoch.
b. There is absence of nonarousal-associated K
complexes and sleep spindles.
EMG = electromyogram; REM = rapid eye movement.
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007.
DaneshGroup.com
 Chapter 3 Sleep Staging in Adults 41

FIGURE 319 Transition from definite

Epoch Epoch stage N2 to definite stage R. Epochs
100 101 102 103 200 201 202 203 contiguous with definite stage R with the
K complex Low amplitude Sleep Low amplitude chin electromyogram (EMG) at the rapid eye
mixed frequency spindle mixed frequency movement (REM) level for the majority of
F4-M1 F4-M1
the epoch and an EEG without sleep spindles
or K complexes (not associated with an
C4-M1 C4-M1 arousal) are scored as stage R even in the
absence of REMs (stage R rule D1; see Table
310). A, Epochs 101, 102, and 103 are
O2-M1 O2-M1 scored as stage R. B, Epoch 202 is scored as
stage N2 by stage N2 continuation rules. The
REM REM
epoch is not stage R because the chin EMG
E1-M2 E1-M2 remains above the REM level.

E2-M2 E2-M2

Chin EMG Chin EMG

Stage Stage Stage Stage Stage Stage Stage Stage

N2 R R R N2 N2 R R
A B

FIGURE 320 Schematics of 30-second

Epoch Epoch epochs illustrate the transition from definite
100 101 102 103 200 201 202 203 stage N2 to definite stage R. A, Epoch 102 is
K complex Sleep K complex
Low amplitude
scored as stage N2 because the epoch
spindle
mixed frequency contains a sleep spindle (stage R rule D2; see
F4-M1 F4-M1
Table 310). B, Epochs 201 and 202 are
Sleep
spindle scored as stage R even in the absence of
C4-M1 C4-M1 rapid eye movements (REMs) because the
Sleep chin electromyogram (EMG) is at the REM
spindle
level, no nonarousal K complexes or sleep
O2-M1 O2-M1 spindles are present in the EEG, and the
epochs are contiguous with definite stage R
REM REM
(stage R rule D3; see Table 310).
E1-M2 E1-M2

E2-M2 E2-M2

Chin EMG Chin EMG

Stage Stage Stage Stage Stage Stage Stage Stage

N2 N2 N2 R N2 R R R
A B

with an epoch of definite stage R and no REMs are present,
the epoch is scored as N2 (Fig. 320A) using REM rule D2
(see Table 310). There are two important points to note.
First, the rule does not require that the SS or KC be in the
first half of the epoch. The rationale is that without other
evidence for a sleep stage transition, stage N2 sleep is present
up until the last KC/SS in the epoch preceding definite stage
R. Second, no REMs are present in the epoch containing the
KC or SS. Epochs with mixtures of KCs and REMs are
discussed later. If the SS had been in the first half of epoch
202, the epoch would be scored as stage N2 by the stage
N2 rules.
In transitions between epochs of definite N2 with chin
EMG at the REM level and definite stage R the intervening
epochs are scored as stage R in the absence of nonarousal-
associated KCs or SSs in the EEG (see Fig. 320B) using
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42 Chapter 3 Sleep Staging in Adults

REM rule D3. This of course assumes that the chin EMG
remains at the REM level.
During epochs in transition from stage N2 to stage R, the
last epoch of definite stage N2 may not necessarily contain a
KC or SS (if the previous epoch contained a KC or SS in the
last half). Figure 321 illustrates a case in which the last KC/
SS was in the last half of an epoch not scored as stage N2. In
this case, epoch 102 following the KC/SS is scored as stage
N2 based on the N2 rules even if the chin EMG is at the REM
level and no KCs or SSs are present. It is important to note
that no REMs are present in epoch 101. Epochs with mix-
tures of KCs and REMs are discussed in the next section.
After epoch 102, subsequent similar epochs are scored as
stage R because the chin EMG is at the REM level and the
EEG remains without KCs or SSs (FAQ V6).
EPOCHS WITH A MIXTURE OF SSs/KCs
AND REMs
In the first period of stage R sleep, epochs often contain a
mixture of sleep stages with SSs or KCs in an epoch that
would otherwise meet criteria for definite REM (low chin
EMG, presence of REMs). Such epochs with REMs are
scored as stage R (Fig. 322 and Table 311). In Figure 322,

FIGURE 321 Schematic of 30-second epochs depict an interruption of stage R

by a K complex not associated with an arousal. Epoch 101 is scored as stage R Epoch
because the K complex occurs in the second half of the epoch. However, the next 100 101 102 103 104 105
epoch is scored as stage N2 (in the absence of rapid eye movements [REMs]). The K complex EEG is low amplitude mixed frequency
following epochs are scored stage R by the rules for transitions between definite F4-M1
unless otherwise depicted

stage N2 and definite stage R. If the K complex in epoch 101 would have occurred
in the first half of epoch 101, the epoch would have been scored as stage N2 (in
the absence of REMs). In this case, epoch 102 would have been scored as stage R C4-M1
using the rules for transition from definite stage N2 to definite stage R. EMG =
electromyogram. O2-M1
REM
REM

E1-M2

E2-M2

Chin EMG

Stage R Stage R Stage N2 Stage R Stage R Stage R

FIGURE 322 Schematics of 30-second

epochs illustrate scoring when epochs meet Epoch Epoch
criteria for definite rapid eye movement 100 101 102 103 200 201 202 203
(REM) sleep except for the presence of K K complex Low amplitude K complex K complex K complex
complexes or sleep spindles. A, Epoch 100 is mixed frequency
F4-M1 F4-M1
scored as stage R because REMs are present
and chin electromyographic (EMG) tone is
low even if a K complex is present. Epoch 101 C4-M1 C4-M1
is scored using the continuation of stage R
rules. Epoch 103 is scored as stage N2
because the K complex is in the first half of O2-M1 O2-M1
the epoch. B, Epoch 203 is scored as stage R REM REM REM REM
because the K complex is in the second half
of the epoch (stage R rule C.1.e; see Table E1-M2 E1-M2
39).
E2-M2 E2-M2

Chin EMG Chin EMG

Stage Stage Stage Stage Stage Stage Stage Stage

R R R N2 R R R R
A B
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 Chapter 3 Sleep Staging in Adults 43

TABLE 311 TABLE 312

Epochs with a Mixture of Sleep Spindles/K Major Points of Rapid Eye Movement Rules
Complexes and REMs CONTINUATION OF
1. Epochs with REMs and low chin EMG tone (at the REM STAGE R END OF REM
level) that would be scored as stage R except for the
Following an epoch of Transition to stage W or N3.
presence of either K complexes or sleep spindles are still
definite stage R, continue Arousal followed by SEM.
scored as stage R.
scoring stage R in the Body movement followed
2. Subsequent contiguous epochs without REMs but absence of REMs. by SEM.
continued low chin EMG are scored by the REM IF Nonarousal KC or SS in first
continuation and end rules (REM rules B and C, Table 3-9) Low chin EMG. half of epoch with no REMs
or stage N2 rules. EEG without SS or (stage N2).
EMG = electromyogram; REM = rapid eye movement. nonarousal KC in the first EMG above REM level for
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American half of the epoch. majority of epoch.
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
EEG = electroencephalogram; EMG = electromyogram; KC = K complex not
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
associated with an arousal; REM = rapid eye movement; SEM = slow eye
Westchester, IL: American Academy of Sleep Medicine, 2007.
movement; SS = sleep spindle.

FIGURE 323 Schematic of 30-second epochs. Stage N1 is scored after an

Epoch arousal during stage N2 sleep. Epoch 201 has an electromyogram (EMG) above the
200 201 202 203 204 rapid eye movement (REM) level. Epoch 203 has a chin EMG at the stage R level
K complex EEG low amplitude mixed and no K complexes (KCs) or sleep spindles (SSs). However, it is scored as stage N1
frequency, no KC or SS
F4-M1 according to FAQ V7.
Arousal
C4-M1

O2-M1
REM

E1-M2

E2-M2

Chin EMG

Stage N2 Stage N1 Stage N1 Stage N1 Stage R

epochs 100 and 200 are scored as stage R. Epoch 101 is
scored as stage R by the REM continuation rule because it
contains no KC or SS. If epoch 100 had the KC in the second
half of the epoch, it would still have been stage R. However,
epoch 101 would be stage N2 by the stage N2 rules (KC or
SS in last half of previous epoch). Note that epoch 203 is
scored as stage R by the continuation of REM rule and the
fact that the KC is in the second half of the previous epoch.
TRANSITIONS BETWEEN STAGE N1 AND
STAGE R (FAQ V7 AASM SCORING RULES)
The AASM scoring manual did not provide rules for the
transition from stage N1 to stage R.
One might assume that epochs intervening between defi-
nite stage N1 with low chin EMG and definite stage R would
be scored similarly to rules for stage N2 to stage R transi-
tions. However, according to an FAQ V7, stage R would be
scored only once REMs are present (definite stage R) (Fig.
323 and Table 312).
EFFECTS OF AROUSALS AND MBMS:
STAGE N2 VERSUS STAGE R RULES
Given the complexity of sleep staging, it is helpful to note
that arousals are treated slightly differently in scoring stage
N2 and stage R. Stage N2 ends when an arousal occurs even
in the absence of an SEM (see Fig. 310). Stage R ends fol-
lowing an arousal only if the arousal is followed by an SEM
(see Fig. 316). In both stage N2 and stage R, the stage is
assumed to end only if an intervening MBM is followed by
an SEM. This assumes that the MBM epoch contains no
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44 Chapter 3 Sleep Staging in Adults

TABLE 313 TABLE 314

When Arousals and Major Body Movements End Scoring Rules for Major Body Movements
Stage N2 and Stage R A. Score stage W if alpha rhythm is present for part of the
YES epoch (even if < 15 sec in duration).

End of stage N2 Arousal B. Score stage W in the absence of alpha rhythm if an

MBM followed by SEM
End of stage R Arousal followed by SEM
MBM followed by SEM
MBM = major body movement; SEM = slow eye movement.
epoch scoreable as stage W either precedes or follows
the epoch with the major body movement.
C. If neither A or B apply, score an epoch with a major
body movement as the same stage as the epoch that
follows it.
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007.

SCORING MAJOR BODY MOVEMENT (MBM) EPOCHS

Major body
Epoch movement Epoch Epoch Epoch
100 200 201 202 200 201 202 300 301 302
K complex
Alpha LAMF

F4-M1
No alpha No alpha No alpha
C4-M1

O2-M1

REMs
E1-M2
REMs
E2-M2

Chin EMG

Stage W Stage N1 Stage W Stage W Stage W Stage W Stage N1 Stage N1 Stage N2 Stage N2

If any alpha If either epoch before If no alpha in MBM

present score or after the MBM epoch epoch and neither
stage W is wake - score MBM preceding or following
epoch as stage W epoch is stage W
- score the MBM epoch
the same as the sleep
stage of the following epoch

FIGURE 324 Schematic of 30-second epochs illustrate scoring rules for major body movements (MBMs). EMG = electromyogram; LAMF = low-amplitude mixed-frequency;
REM = rapid eye movement.

alpha. If the epoch contains alpha, it is scored as stage W and
either stage N2 or stage R end (transition to stage W) (Table
313).
MAJOR BODY MOVEMENTS
An MBM is defined as movement and muscle artifact obscur-
ing the EEG for more than half an epoch to the extent that
the sleep stage cannot be determined (Table 314). The rules
for scoring epochs containing MBM are illustrated in Figure
324. If any alpha is present in the MBM epoch, it is staged
as stage W. The MBM epoch is also scored as stage W if either
the epoch preceding or the one following the MBM epoch
is scored as stage W. Finally, if the previous possibilities
do not apply, the MBM epoch is scored the same as the
following epoch.
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 Chapter 3 Sleep Staging in Adults 45

TABLE 315 TABLE 316

Arousal Rules Summary of Arousal Rules
NREM AROUSAL CRITERIA DURATION INCREASE IN
Score an arousal during sleep stages N1, N2, and N3 if there EEG (NREM OR OF EEG SUBMENTAL
is an abrupt shift of EEG frequency including alpha, theta, REM) CHANGE CHIN EMG
and/or frequencies greater than 16 Hz (but not spindles) NREM Abrupt shift in At least None required.
that lasts at least 3 seconds, with at least 10 seconds of EEG frequency 3 sec
stable sleep preceding the change. including
REM At least At least 1 sec and
REM AROUSAL CRITERIA alpha, theta,
3 sec concurrent
and
Score an arousal during sleep stage R if there is an abrupt with shift in
frequencies
shift of EEG frequency including alpha, theta, and/or EEG frequency.
greater than
frequencies greater than 16 Hz (but not spindles) that lasts 16 but NO
at least 3 seconds, with at least 10 seconds of stable sleep spindles
preceding the change.
EEG = electroencephalogram; EMG = electromyogram; NREM = nonrapid
AND eye movement; REM = rapid eye movement.
There is a concurrent increase in submental EMG lasting at
least 1 second in addition to the required EEG changes.
EEG = electroencephalogram; EMG = electromyogram; NREM = nonrapid
eye movement; REM = rapid eye movement.
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007.

F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin1-Chin2

FIGURE 325 An arousal during nonrapid eye movement (NREM) sleep. A 30-second tracing is depicted. Note that the K complex was NOT included in criteria for the arousal.
In addition, an increase in the chin electromyogram (EMG), although present, is NOT required.

Arousal Rules
Arousals are transient phenomenon that may lead to wake-
fulness or only briefly interrupt sleep. They are worth scoring
because patients with frequent arousals may have daytime
sleepiness even if the total sleep duration is normal. An
arousal is scored during sleep stages N1, N2, and N3 (NREM
sleep) if there is an abrupt shift of EEG frequency including
alpha, theta, and/or frequencies greater than 16 Hz (but not
spindles) that lasts at least 3 seconds, with at least 10 seconds
of stable sleep preceding the change (Tables 315 and 316).
An arousal is scored during REM sleep if there is a concur-
rent increase in submental EMG lasting at least 1 second in
addition to the EEG changes required for NREM arousals.
Because alpha bursts during stage R are common, the addi-
tional requirement of an increase in chin EMG was added.
Figure 325 illustrates an arousal during NREM sleep. In
this example, the chin EMG also increases but this is not part
of the criteria used to score an arousal. Note that there is a
shift in EEG frequency greater than 3 seconds that does not
include spindle activity. Also note that, although KCs may
be associated with arousals, the presence of a KC alone (no
3-sec shift in EEG frequency) is not considered to indicate
an arousal even if it is associated with an increase in the chin
EMG. Figure 326 illustrates an arousal from stage R. Here
both the EEG and the chin EMG changes meet arousal cri-
teria. Figure 327 illustrates an epoch of stage R with a burst
of alpha activity that is not concurrent with the brief increase
in chin EMG activity and an arousal is not scored. Bursts of
alpha are common during stage R. The alpha activity during
REM sleep is often about 1 Hz slower than during nonrapid
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46 Chapter 3 Sleep Staging in Adults

100 V

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2
Chin EMG

FIGURE 326 Stage R with an arousal. A 30-second epoch is depicted. Note that the increase in chin electromyogram (EMG) is greater than 1 second (the criteria for arousal in
stage R is at least 1 sec).

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin1-Chin2

FIGURE 327 A 30-second epoch of Stage R is depicted. There is a burst of alpha activity after REMs. This is not an arousal. Note that the increase in EMG is less than 1 second
and not concurrent with the burst of alpha.

eye movement (NREM) sleep. The burst of chin EMG activ-
ity in Figure 327 is less than 1 second in duration and there
is no concurrent 3 seconds or longer abrupt shift in EEG
frequency.
Although the choice of a 3-second EEG change appears
arbitrary, studies have shown that reliability of scoring arous-
als is better with a 3-second EEG change than with shorter
durations of required EEG change.5 Although not specified
in the recent AASM scoring manual, a previous American
Sleep Disorders Association (AADA) task force produced a
number of additional recommendations for the scoring of
arousals.6 A summary of the most important points follows:
3. Artifacts, KCs, or delta waves are not scored as arousals
unless accompanied by an EEG frequency shift, as defined
previously.
4. Intrusions of alpha activity less than 3 seconds in duration
into NREM sleep at a rate greater than one burst per 10
seconds is not scored as an EEG arousal. Three seconds
of alpha sleep is not scored as an arousal unless a 10-second
episode of alpha-free sleep precedes.
5. Transitions from one stage of sleep to another are not
scored as arousals unless they meet the criteria indicated
previously.

1. If one arousal is scored, at least 10 seconds of continuous REFERENCES

intervening sleep must be present before a second arousal
1. Rechtschaffen A, Kales A (eds): A Manual of Standardized Ter-
can be scored. minology Techniques and Scoring System for Sleep Stages of
2. Arousals cannot be scored based on changes in submental Human Sleep. Los Angeles: Brain Information Service/Brain
EMG alone. Research Institute, UCLA, 1968.
DaneshGroup.com

2. Caraskadon MA, Rechschaffen A: Monitoring and staging
human sleep. In Kryger MH, Roth T, Dement WC (eds): Prin-
ciples and Practice of Sleep Medicine, 2nd ed. Philadelphia: WB
Saunders, 2005, pp. 13591377.
3. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring
of Sleep and Associated Events: Rules, Terminology and Techni-
cal Specifications, 1st ed. Westchester, IL: American Academy of
Sleep Medicine, 2007.
Chapter 3 Sleep Staging in Adults 47
4. Silber MH, Ancoli-Israel S, Bonnet MH, et al: The visual scoring
of sleep in adults. J Clin Sleep Med 2007;15:121131.
5. Bonnet MH, Doghramji K, Roehrs T, et al: The scoring of arous-
als in sleep. Reliability, validity, and alternatives. J Clin Sleep
Med 2007;3:133145.
6. American Sleep Disorders AssociationThe Atlas Task Force:
EEG arousals: scoring rules and examples. Sleep 1992;15:
174184.
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Biocalibration, Artifacts, and
Common Variants of Sleep
Chapter Points
Recording a technically adequate biocalibration is an
important part of every sleep study. Careful attention
to the recorded biocalibration by the scorer or
physician reviewing the study is essential for
identifying the individuals pattern of eyes-open and
eyes-closed wakefulness as well as the appearance of
eye movements. The biocalibration may help the
scorer differentiate stage W with REMs from stage R
when the chin EMG is at a low level in both sleep
stages.
A 60-Hz artifact is recognized as a ropelike pattern. If
there is a large increase in the signal amplitude when
the 60-Hz notch filter is turned off (especially with a
100 Hz high filter setting), this implies significant 60-Hz
contamination of the signal. High electrode impedance
is a common cause of 60-Hz artifact.
The ideal electrode impedance is less than 5 K
(acceptable <10 K).
ECG artifact can be minimized by correct mastoid
electrode placement. During review, ECG artifact can
be minimized by using an average of the mastoids
(e.g., F4-Avg) or linking the electrodes.
Sweat artifact (sway) can be minimized by cooling the
patient down or using different derivations if
movement of one of the mastoid electrodes is causing
the problem.
Electrode popping is a serious artifact and requires
replacement or fixing the faulty electrode (or
preventing movement of the electrode with each
breath) during recording.
A large amount of sleep spindle activity may be a clue
that the patient is taking a BZRA.
Eye movements may persist in stage N2 sleep in
patients taking SSRIs.
Prominent alpha activity can be seen riding on top of
SWA in alpha-delta sleep. Increasing the viewing
window to 10 seconds and counting waveforms can
help confirm that prominent alpha activity is present.
Chapter 4
CALIBRATIONS AND BIOCALIBRATIONS
Calibrations
Calibration was especially critical during paper recording to
document the individual amplifier sensitivity, polarity, and
filter settings because these could not be changed once data
were recorded. In the digital era, electroencephalographic
(EEG), electro-oculographic (EOG), and electromyographic
(EMG) data are acquired at a default gain and with a wide
bandpass (e.g., 0.03 and 100 Hz, respectively). The desired
channel sensitivity and filter settings for the display of indi-
vidual channels (traces) can be changed during acquisition
and review. In the paper era (Fig. 41), calibration was
usually performed by sending a square wave voltage pulse
(typically 50 V). The sensitivity control was adjusted until
a 50-V signal produced a 10-mm pen deflection (others
used 75 V for 10 mm). Digital systems today often send a
sine wave signal of standard frequency (5 or 10 Hz) and
peak-to-peak voltage (100500 V) to the amplifier to docu-
ment digital system accuracy (Fig. 42). Whereas the analog
amplifier gain used in digital systems usually cannot be
adjusted except by the manufacturer, the computer program
can change calibration factors to more accurately display
the recorded data. If large adjustments are necessary, the
program will often provide notification that amplifier service
is needed.
The output of each individual AC amplifier can be scaled
by calibration factors so that they provide exactly equivalent
outputs from the calibration signal. In Figure 42, a 500-V
calibration signal results in slightly different outputs from
the amplifiers processing the C4-Ref and M1-Ref signals. Cali-
bration factors are selected to scale the outputs to the input
standard. After scaling, the digital values used for display
match the input calibration voltage and, even more impor-
tant, the two amplifiers deliver the same exact output from
the calibration signal. This improves common mode rejec-
tion during referential recording. That is, the same signal
applied to both amplifiers should result in zero output when
the derivation using them is displayed (digital subtraction).
Of note, the display filter settings can change signal
amplitude depending on the calibration signal frequency.
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50 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep

One advantage of a 5-Hz signal is that it is minimally changed
by typical low- and high-frequency filter settings used in
EEG derivations.
Calibration of DC signals (Fig. 43) is usually performed
using a two-point calibration method. This is performed by
sending a lower and higher signal (usually 0 and 1 V or 1
and 1 V) and specifying the parameter values corresponding
to the two voltages. For example, a positive airway pressure
device and analog module outputs 0 V for 0 cm H2O pres-
sure and 1 V for 30 cm H2O. The device would be directed
to send 0 V to the digital system and 0 cm H2O pressure is
specified using the polysomnography (PSG) software. Then
1 V is sent and 30 cm H2O is specified. There is usually an
option to type in the expected voltage or to actually measure
50 V
Sens
(V/mm) LF
1 cm
EEG 5 0.3 30
the voltage sent by the device at each of the two calibration
points. For example, when the low calibration voltage is sent
the set low button is pushed. This action displays the actual
voltage in the voltage input 1 window (Fig. 4-3) and sends
value to the computer for computation of the calibration
factors. A similar procedure is performed when the high
calibration voltage is sent. The computer then determines
and stores the calibration factors.
Biocalibrations
Biocalibration (Table 41 and Fig. 44) is an important part
of every PSG recording, but the value of the procedure is
often unrecognized. During the biocalibration, signals are
recorded while the patient performs maneuvers that verify
that the monitoring equipment, electrodes, and sensors are
working properly. The impedance of all EEG, EOG, and
EMG electrodes should be checked. For the reviewer, noting
the patients EEG, EOG, and EMG pattern of eyes-open and
HF
DC Input 1

EEG 5 0.3 30 Voltage input 1 Voltage input 2

0 Set 1 Set
EOG 5 0.3 30 low high
Digital value 1 Digital value 2
EOG 5 0.3 30 0 30

Channel label
Chin EMG 10 10 30 cm H2O Units
CPAP pressure

FIGURE 41 Example of calibration using analog amplifiers and paper recording. A
square wave voltage signal of 50 V is sent by pushing a button on the amplifier system
and then releasing the button. The effects of the filters being used on the pen deflections
can be seen (Chin EMG [electromyogram] channel). EEG = electroencephalogram; EMG
= electromyogram; EOG = electro-oculogram; HF = high frequency; LF = low frequency.
FIGURE 43 Schematic of computer screen used to calibrate DC signals. Most systems
have an option to ask the system to measure the voltage input (Get low value) rather
than simply enter it. So voltage input 1 can be sent to the polysomnography (PSG)
system and the actual voltage measured (acquired). CPAP = continuous positive airway
pressure.

FIGURE 42 Schematic representation of scaling C4-M1  Cal1 (C4-Ref) Cal2 (M1-Ref)

of amplifier outputs so that they both are accurate  Cal1 C4 Cal2 M1 Ref (Cal1-Cal2)
and provide the same output from the calibration 500 V C4 Cal1 C4 Cal2 M1
signal. Here, Cal1 and Cal2 are the calibration
factors and Ref is the reference electrode used for Ideal Ref
M1 C4-M1
referential recording. A calibration signal of
500 V is sent to all amplifier inputs. Ref Digital subtraction
of two outputs

500 V C4
510 V
Actual Ref C4-M1
M1
502 V
Ref

Cal1
500 V C4 500  500
510 V 510
After
Ref
calibration Cal2 C4-M1
M1
500  500
502 V 502
Ref
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 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep 51

TABLE 41
Biocalibration Procedure
COMMAND WHAT TO CHECK AND OBSERVE
While looking straight ahead, Quality of alpha production.
close your eyes Slow eye movements.
Open your eyes Attenuation of alpha.
EEG of wakefulness.
Pattern of eyes-open stage W.
REMs during wake.
Look right Integrity of eye electrodes.
Look left Pattern of the patients REMs and blinks.
Look up Ability to detect horizontal and vertical eye movements.
Look down
Blink eyes
Grit teeth Function of chin EMG.
Sensitivity should be adjusted so that some activity is present during relaxed wake.
Breathe in, breathe out Airflow sensors show airflow working properly, adjust sensitivity.
Proper polarity for all respiratory sensors. That is, during inspiration, all deflections are
upward or downward (depending on sleep center protocol).
Adjust sensitivity of chest and abdomen tracings.
Hold your breath Ability to detect apnea.
Wiggle your right toe Ability to detect leg movements.
Wiggle your left toe Adjust leg derivation sensitivity so movements can be easily seen in both legs.
EEG = electroencephalogram; EMG = electromyogram; REMs = rapid eye movements.

Eyes closed Eyes open Look up Look down Look left Look right Blink Grit teeth/chew

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

FIGURE 44 Biocalibration of EEG, EOG, and chin EMG derivations.

eyes-closed stage W can help with recognition of this sleep
stage during the recording and during scoring of sleep. It is
especially important to know whether the person being
recorded generates alpha activity with eye closure because
this affects the scoring criteria for stage W and stage N1 (see
Chapter 3).
Figure 45 shows a portion of the biocalibration proce-
dure in a patient with a prior left eye enucleation. Hopefully,
technologists notes and patient history would have alerted
the reviewing physician to this situation. However, looking
at the biocalibrations would also alert the physician that
stage R sleep would have an unusual appearance.
ARTIFACTS
Artifacts in the EEG, EOG, and EMG derivations due
to inadequate electrode application or the effects of
patient movement and the environment are common in
polysomnography.14 It is essential that they be recognized
during recording to allow for intervention by the sleep
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52 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep

Look up Look down Look left Look right Blink

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin EMG

FIGURE 45 Biocalibration in a patient with prior left eye enucleation. The deflections in the frontal derivations are noted because these electrodes are relatively
close to the eyes compared with other electrodes. The grid lines are 1 second apart. EMG = electromyogram.

TABLE 42
Electrode Popping Artifact
Electrode popping artifact is a sudden, high-voltage
deflection occurring at regular intervals, usually
coincident with respiration.
Electrode popping artifact is due to an electrode pulling
away from the skin or the drying of electrode gel or paste.
Noting the affected derivations can identify the problem
electrode:
Several derivations with a common electrode.
One derivation with a unique electrode.
Reapplication of the problem electrode, the addition of
electrode paste, or change in the position of the electrode
wire is indicated during recording.
Review using a derivation not including the problem
electrode will usually allow staging of sleep.
technologist. Postrecording maneuvers to minimize the
effects of some artifacts on sleep staging are often possible.
Electrode Popping
Electrode popping is a common and severe artifact that
makes the staging of sleep very difficult (Table 42). It is
characterized by sudden, high-amplitude deflection (often
with channel blocking) secondary to an electrode pulling
away from the skin (sudden loss of signal). The popping
often tends to be regular and corresponds to body movement
during breathing. Electrode popping may also be caused by
the patient lying on one mastoid electrode or pulling on the
wire connecting the electrode with the electrode box during
respiration. For example, if the wire runs under the patients
body or through chest or abdominal bands, patient move-
ment or respiration can pull on the electrode wire. Popping
also can occur if the electrode gel dries out during the night.
At the time of recording, adding electrode gel or reapplica-
tion of the problem electrode may eliminate the problem.
Postrecording, the artifact can frequently be handled by
switching to an alternative derivation that does not use the
problem electrode. For example, if O2 is the problem, the
exploring occipital electrode is switched to O1. This is one
reason that redundant electrodes are routinely placed.
In Figure 46, regular high-voltage deflections are noted
in all derivations containing M1. Therefore, the problem is
most likely in electrode M1. Video monitoring confirmed
that the patient was sleeping on the left side. After changing
the reference electrode to M2 (using derivations F3-M2,
C3-M2, O1-M2, E1-M2, and E2-M2), the problem was elimi-
nated. Displaying F4-M2, C4-M2, O2-M2 would also eliminate
the artifact. However, using an exploring electrode opposite
the reference is preferable because this produces a larger
voltage signal. In fact, F3-M2, C3-M2, and O1-M2 are the alter-
nate derivations recommended by the American Academy
of Sleep Medicine (AASM) scoring manual. If an electrode
in the standard derivation fails, use of corresponding
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 F4-M1

C4-M1

O2-M1
Chapter 4

E1-M2

E2-M2

Chin

Airflow

FIGURE 46 Electrode popping artifact. The problem electrode is M1. The artifact is present only in derivations using the electrode M1, and M1 is the only electrode common to all affected derivations.
Biocalibration, Artifacts, and Common Variants of Sleep
53

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54 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep
electrode in the alternate derivation set for sleep monitoring
is recommended (see Chapter 1).
60-Cycle Artifact
A 60-cycle artifact in EEG, EOG, or EMG tracings is a
common problem in sleep study recording (Table 43). It is
caused by 60-Hz electrical activity from power lines con-
taminating the recorded signal. A 60-Hz artifact can be
minimized by correct application of electrodes and proper
design of the sleep laboratory. EEG amplifiers are AC-coupled,
which allows them to record low-voltage EEG activity while
rejecting unwanted and sometimes higher-voltage AC or DC
activity. Differential amplifiers can record low-voltage physi-
ologic signals by amplifying the difference in voltage between
two electrodes while rejecting the common-mode signal
consisting of higher-voltage, 60-Hz, background activity.
When recording the voltage difference between two elec-
trodes, the background AC activity is rejected only if the
electrode impedances are low and fairly equal. Although
most AC amplifiers have notch filters to minimize 60-Hz
activity, these filters may not prevent prominent 60-Hz activ-
ity when electrode impedances are very different (usually
one defective electrode has very high impedance). The ideal
impedance of electrodes is below 5 K (acceptable <10 K).
Electrode impedance should be checked by the sleep tech-
nician after electrode application before recording starts.
Routine use of 60-Hz notch filters makes recognition of
60-Hz contamination more difficult and is not recom-
mended. It should be appreciated that use of a 35-Hz high-
frequency filter for EEG and EOG derivations significantly
attenuates 60-Hz activity. The effect of adding or removing
the notch filter is more prominent in chin and leg EMG
derivations that use a high-frequency filter of 100 Hz.
The sudden appearance of 60-Hz artifact usually means
one electrode is faulty. In the days of paper PSG, the artifact
caused a characteristic humming of the pens as they
oscillated at 60 cycles/sec. If a 60-Hz contamination of a
TABLE 43
60-Hz Artifact
60-Hz artifact often produces a thick band or ropelike
appearance in the tracing.
60-Hz contamination of the recorded signal may not be
recognized if both a 35-Hz high-frequency filter and a
60-Hz notch filter are used for display.
Recording with 60-Hz filter off will increase the ability to
recognize the presence of 60-Hz signal contamination
(usually a clue that an electrode needs replacement).
60-Hz artifact is more apparent with a high-frequency
filter of 100 Hz.
If turning on and off the 60-Hz notch filter significantly
reduces (increases) signal amplitude, this is another clue
that 60-Hz contamination is present in a given derivation.
derivation is significant, turning off the 60-cycle filter will
significantly increase the amplitude of the artifact (if a high
filter of 100 Hz is used for the derivation). A 60-Hz artifact
can also be recognized on the usual 30-second view by a very
dense uniform squared off or ropelike tracing that does not
vary. If 60-Hz artifact is due to a single electrode, it should
be replaced during recording. Using a different display deri-
vation after postrecording may solve the problem. In Figure
47, prominent 60-Hz artifact is noted in the chin derivation
and produces a band or ropelike tracing. Application of the
60-Hz filter dramatically reduced the amplitude consistent
with a significant amount of 60-Hz artifact. The problem was
the chin2 electrode. When the derivation was changed, the
artifact was eliminated even without the use of a 60-Hz filter.
The ideal intervention would have been replacement of the
chin2 electrode.
Slow-Frequency (Sweat) Artifact
Slow-frequency (sweat) artifact is characterized by a slowly
undulating movement of the baseline of affected channels
(Table 44 and Fig. 48). The movement may or may not be
synchronous with the patients respiration. When in-phase
with the patients respiration, the artifact also is called respi-
ratory artifact. Sweat artifact is believed to be secondary to
the effects of perspiration. Sweat alters the electrode poten-
tial, thereby producing an artifact that mimics delta waves
and results in overscoring of stage N3. When the artifact is
not present in all channels, the artifact may be secondary to
pressure on an electrode (or pulling on the electrode). In this
case, the artifact is usually coming from one or more elec-
trodes on the side on which the patient is lying. For example,
if the patient is sleeping with the left side down, derivations
containing M1 would be affected but not those containing
M2. If a single electrode is the problem, changing derivations
to one that does not use the faulty electrode may be a solu-
tion. If this does not work or if the problem involves all
derivations, other actions are necessary. Options include
reducing the room temperature, uncovering the patient,
and/or using a fan. As a last-ditch alternative, the setting of
TABLE 44
Slow-Frequency (Sweat) Artifact
A slowly undulating signal (sway) is typical of sweat
artifact.
If sweat artifact is present in all derivations and the room
or patient is warm, cooling of the patient should be
attempted.
If sway is present only in derivations utilizing a given
mastoid electrode, the artifact may be due to movement
of the mastoid electrode during respiration.
Slow-frequency artifact may make scoring stage N3 very
difficult.
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 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep 55

FIGURE 47 60-Hz artifact. A, The 60-Hz filter is off. Note the band
or ropelike appearance of the chin EMG. B, Turning on the 60-Hz
A 60 Hz filter OFF
notch filter dramatically reduced the amplitude consistent with the
presence of 60-Hz artifact. C, When chin2 was replaced with chin3,
F4-M1 the EMG amplitude decreased dramatically and the epoch containing
C4-M1 the 15-second fragment was scored as stage R (REM [rapid eye
movement] sleep). The impedance of the faulty chin2 electrode was
O2-M1 55 K (desired <5 K).
E1-M2

E2-M2

Chin1-Chin2

B 60 Hz filter ON

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin1-Chin3

C 60 Hz filter OFF
Chin1-Chin3

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2
Chin

FIGURE 48 Slow-frequency (sweat) artifact is present in derivations containing both M1 and M2. Lowering the room temperature eliminated the problem.

the low-frequency filter may be increased (e.g., from 0.3 to

1). Unfortunately, this maneuver decreases the amount of
slow wave activity (SWA) that is depicted, but still may be
preferable to a totally unscorable record. Sweat artifact can
be prevented by maintaining a low room temperature, espe-
cially when very obese or heavily perspiring patients are
studied. One can quickly add a blanket, but cooling down a
sleep room takes more time.
ECG Artifact
ECG artifact is one of the most common and easily recogniz-
able recording artifacts (Table 45). It can be identified by
sharp deflections in the signals of affected channels corre-
sponding exactly in time to the QRS of the ECG tracing.
Fortunately, this artifact does not usually interfere with
visual sleep staging because the artifact does not mimic usual
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56 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep
TABLE 45
Electrocardiogram Artifact
ECG artifact can be easily recognized as sharp deflections
in the affected leads corresponding to the QRS complex
in the ECG lead.
Proper application of the mastoid electrodes and double
referencing (using an average of M1 and M2) can prevent
or minimize this artifact.
ECG = electrocardiogram.
EEG patterns. It can mimic spike activity. The artifact can be
minimized by placing the mastoid electrodes sufficiently
high (behind the ear) so that they are over bone instead of
neck tissue (fat). Either linking the two mastoid electrodes
physically by a jumper cable at the electrode box or using
derivations in which the reference electrode is an average of
M1 and M2 can minimize ECG artifact. This is also some-
times called double-referencing. These techniques work
because, if the ECG voltage vector is toward one mastoid, it
is away from the other. Hence, the ECG components of the
two signals tend to cancel each other out. In Figure 49, ECG
artifact is prominent in all derivations except one using an
average of M1 and M2 (F4-AVG). Two small dark circles in
E1-M2 mark the artifact. In the tracing shown, ECG artifact
is larger than desirable, but the record still can be scored.
Pulse Artifact
Pulse artifact is similar to ECG artifact except that, rather
than electrical interference, the artifact is due to movement
of an electrode caused by the pulsation of an underlying
artery. Because the arterial pulse occurs after the QRS
complex, the timing of the artifact is delayed after each QRS.
Figure 410 shows the ECG (square) artifact and pulse arti-
fact (circles).
Muscle Artifact
Muscle artifact in the EEG and EOG is due to increased
muscle tone in the muscles underlying the EEG and EOG
electrodes. Often, this will resolve as the patient relaxes and
falls asleep (Fig. 411).
Snoring/Respiratory Chin EMG Artifact
An increase in chin EMG amplitude can sometimes be seen
with each inspiration (Fig. 412). This is especially common
when the upper airway resistance is high (e.g., during
snoring). The genioglossus (tongue protruder) has inspira-
tory EMG activity that increases with more negative upper
airway pressure.5 The muscle attaches to the mandible in the
midline. EMG electrodes below the mandible may pick up
the increased inspiratory activity of the genioglossus or other
nearby neck muscles associated with increased inspiratory
effort induced by a high upper airway resistance. Another
TABLE 46
Alpha Sleep Anomaly
Alpha sleep anomaly is characterized by the persistence
of prominent alpha activity during NREM sleep (especially
stage N3 sleep).
The pattern has been associated with chronic pain
syndromes or psychiatric disorders but can occur in
normal individuals.
Alpha anomaly makes scoring stage N1 and sometimes
stage N2 sleep difficult.
Scoring stage N3 is less problematic.
NREM = nonrapid eye movement.
possible cause is simply movement of chin electrode wires
with each inspiration. Nasal pressure monitoring is discussed
in Chapter 7.
Eye Movement Artifact
Eye movements can be picked up in the frontal derivations
because F3 and F4 are fairly close to the eyes. In Figure 45,
note the deflections in F4-M1 associated with eye movements.
This is usually easily recognized by the apperance of frontal
derivation deflections when deflections in the EOG deriva-
tions are seen.
Ground Artifact
If one of the two inputs to a differential amplifier (say G1 in
Fig. 21) is disconnected (electrode unattached), the ampli-
fier really records the difference between G2 and the ground
electrode. Because the ground electrode is typically attached
to the forehead near the eyes, one can see deflections associ-
ated with eye movements in channels in which they are
usually not visible (say, O2-M1). Usually, considerable 60-Hz
artifact would also be seen. However, if the display of the
derivation uses a 35-Hz high-frequency filter, which attenu-
ates a great deal of the 60-Hz signal contamination, this
might be missed. Therefore, the appearance of eye move-
ments in unusual channels should trigger the technologist or
reviewer to consider whether ground artifact is present.
COMMON VARIANTS SEEN DURING
SLEEP MONITORING
Alpha NonRapid Eye Movement Sleep Anomaly
The finding of prominent alpha activity (813 Hz) during
nonrapid eye movement (NREM) sleep is often called alpha
sleep, alpha intrusion, or alpha-delta sleep (if noted in asso-
ciation with stage N3). It makes sleep staging more challeng-
ing (Table 46 and Fig. 413). The alpha activity may be
more prominent in frontal than occipital regions in contrast
to the typical alpha rhythm. When viewing a tracing of
alpha-delta sleep in a 30-second window, there is the
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F4-AVG

F4-M1

C4-M1
Chapter 4

O2-M1

E1-M2

E2-M2

Chin EMG

ECG

FIGURE 49 Electrocardiogram (ECG) artifact is present in all derivations except for the top one using an average of M1 and M2 as the reference (F4-AVG). Black dots point out two deflections from the ECG artifact. EMG = electromyogram.
Biocalibration, Artifacts, and Common Variants of Sleep
57

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58 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep

F4-M1

ECG

1 sec

FIGURE 410 Pulse artifact (circles) follows the electrocardiogram (ECG) artifact in F4-M1
(squares) and the QRS in the ECG. The spike (narrow) deflection in the encephalogram (EEG)
corresponds to the QRS in the ECG. This is followed by a hump in the EEG associated with the
arterial pulse.

Grit teeth Relax 60 Hz filter ON

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin EMG

FIGURE 411 Muscle artifact. The patient was asked to grit his teeth then relax. Adding the 60-Hz filter makes little difference because the majority of signal activity is not due
to 60-Hz signal contamination.

impression of a background of diffuse higher-frequency
activity. By changing to a 10-second window, one can count
the smaller wave forms in 1 second that are superimposed
on slower activity (alpha 813 Hz).
First described in 1973 by Hauri and Hawkings,6 alpha-
delta sleep was once thought to be a characteristic finding
associated with fibromyalgia (FM).7 However, alpha sleep is
not seen in all patients with FM and can occur in patients
with other psychiatric and chronic pain disorders. Mahow-
ald and Mahowald8 concluded that alpha sleep was not
specific for FM and was not necessarily associated with
symptoms of myalgia. It was present in 15% of normal sub-
jects in undisturbed sleep.
Roizenblatt and coworkers9 also studied patients with FM
off medications and normal controls. Alpha rhythm was
noted during sleep in 70% of FM patients and 16% of normal
individuals. Three distinct patterns were noted: phasic alpha
patternsepisodic alpha occurring simultaneously with
delta activity (70% FM, 7% controls); tonic alpha continu-
ously present throughout NREM sleep (20% of FM and 9%
of controls); and low alpha pattern seen in 30% of FM
patients and 84% of controls. The phasic pattern was
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 Chapter 4
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
Snore
Nasal
pressure
Nasal oral
therm flow
FIGURE 412 Snoring artifact is noted in the chin electromyogram (EMG). Note the evidence of snoring in the snore microphone and in the nasal pressure.
TABLE 47
Drug Spindles
Frequent and prominent sleep spindle activity is often
noted in patients taking benzodiazepine receptor
agonists.
Sleep spindle frequency is often at the higher end of the
sleep spindle range.
The pattern may be a useful clue that a hypnotic
medication was taken before the sleep study.
associated with lower sleep efficiency, decreased slow wave
sleep, longer morning pain, and subjective feeling of super-
ficial sleep. Further research is needed to confirm the
findings.
Drug Spindles
Patients who are taking benzodiazepine receptor agonists
(BZRAs) often have increased sleep spindle activity (Table
47 and Fig. 414).1012 Sleep spindle activity has a frequency
of 11 to 16 Hz. Drug spindles often have a frequency in the
higher end of the range. Benzodiazepines are associated with
a decrease in slow wave amplitude (less stage N3 sleep) and
an increase in higher EEG frequencies.13 The nonbenzodiaz-
epine BZRAs (zolpidem, zaleplon, eszopiclone) tend to have
less effect on the amplitude of slow waves and, therefore, do
not usually decrease the amount of stage N3 sleep. However,
they do increase EEG frequencies during sleep, including
sleep spindle activity.
Eye Movements Associated with Selective
Serotonin Reuptake Inhibitor Medications
Slow eye movements are typically present during stage W
with the eyes closed and during stage N1. They typically
Biocalibration, Artifacts, and Common Variants of Sleep 59
TABLE 48
Eye Movements Associated with Selective
Serotonin Reuptake Inhibitor Medications
Prominent slow and rapid eye movement activity may be
seen in stage N2 (and less commonly in stage N3) in
patients taking SSRI antidepressants.
The SSRI eye movements can be a mixture of slow and
more rapid eye movements.
SSRI = selective serotonin reuptake inhibitor.
vanish with the onset of stage N2. However, in patients
taking selective serotonin reuptake inhibitors (SSRIs), a
mixture of slow and more rapid eye movements may persist
into stage N2 or stage N3.13,14 Because this phenomenon was
first descibed with patients on fluoxetine, such eye move-
ments are often called Prozac eyes. Figure 415 shows a
tracing from a patient on fluoxetine (Table 48).
Transient Muscle Activity during Rapid Eye
Movement Sleep
Stage R (REM [rapid eye movement] sleep) is characterized
by low chin EMG tone; that is, the baseline chin EMG activ-
ity in the chin derivation is no higher than in any other sleep
stage and usually at the lowest level of the entire recording.
However, transient bursts of EMG activity termed transient
muscle activity (TMA; formerly called phasic activity),
consisting of short irregular bursts of EMG activity (usually
<0.25 sec), may be seen in the chin or anterior tibial EMG
derivations during stage R15,16 (Table 49). This activity is
maximal in association with bursts of REMs (Fig. 416). In
normal individuals, twitching in muscles may occur but
usually no gross motor movements.
TMA is termed excessive TMA in REM sleep when more
than 50% of 10 sequential 3-second miniepochs contain such
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Chapter 4

1 sec

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2
Biocalibration, Artifacts, and Common Variants of Sleep

Chin EMG

FIGURE 413 Alpha sleep. Prominent alpha activity is diffusely present in this 30-second epoch of stage N3 sleep. Note that the alpha activity is more prominent in the frontal and central derivations. A 1-second enlargement is shown.
EMG = electromyogram.

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 1 second

F4-M1

C4-M1
Chapter 4

O2-M1

E1-M2

E2-M2

Chin EMG

FIGURE 414 Prominent sleep spindle activity is noted in this 30-second tracing. A 1-second enlargement is shown. Unlike the diffuse alpha activity in Figure 413, the sleep spindles are noted in discrete bursts. EMG = electromyogram.
Biocalibration, Artifacts, and Common Variants of Sleep
61

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62 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep

100 V
1 sec F4-M1
C4-M1
O2-M1
E1-M2
E2-M2

Chin EMG

FIGURE 415 A 30-second tracing of a patient taking fluoxetine. Eye movements persist into stage N2 sleep. EMG = electromyogram.

100 V
F4-M1
1 sec
C4-M1
O2-M1
E1-M2
E2-M2
Chin1-Chin2

FIGURE 416 Bursts of EMG activity are noted on the background of reduced tonic chin EMG activity. The transient muscle activity often occurs in association with bursts of eye
movements. Similar activity is not uncommon in normal individuals but is often more prominent in patients taking selective serotonin reuptake inhibitors.

TABLE 49 amplitude four times the background EMG activity). The

Transient Muscle Activity during Stage R mean percentages of 2-second REM sleep bins containing
phasic activity in the control group and SSRI groups were
Short irregular bursts of chin EMG activity (usually
<0.25 sec). 2.36% and 9.54%, respectively (P = .07). See Chapter 12 for
information on scoring the EMG activity associated with the
Most often seen in association with bursts of eye REM sleep behavior disorder.
movements.
Commonly seen in patients taking SSRI medications. CLINICAL REVIEW QUESTIONS
Excessive TMA exists if >50% of 10 sequential 3-second 1. Given tracing A in Figure 417, what should you do while
miniepochs contain such activity with an amplitude at reviewing the study?
least four times greater than the background EMG activity. A. Change to F3-M2, C3-M2, O1-M2.
EMG = electromyogram; SSRI = selective serotonin reuptake inhibitor; B. Change to F4-M2, C4-M2, O2-M2.
TMA = transient muscle activity.
C. Measure the impedance of electrodes.
D. Link M1 and M2 (double reference).
activity with an amplitude at least four times greater than the
background EMG activity. Excessive TMA (or an increase in 2. Based on tracing B in Figure 417, what should you do?
tonic EMG activity during stage R) is said to represent REM A. Change low-frequency filter from 0.3 to 0.5 Hz.
sleep without atonia. If REM sleep without atonia is com- B. Cool the patient down.
bined with abnormal dream-enacting behavior documented C. Change to F3-M2, C3-M2, O1-M2.
at the time of PSG (ideally video PSG) or by history, this is
D. Change low-frequency filter from 0.3 to 1.0 Hz.
consistent with the presence of the REM sleep behavior dis-
order (see Chapter 28).17 The EMG finding alone does NOT 3. What artifact(s) are shown in tracing C in Figure 417?
allow one to make the diagnois of the REM sleep behavior A. ECG artifact.
disorder. Patients on SSRIs are especially likely to show
B. Pulse artifact.
TMA, although they usually do not meet criteria for exces-
sive TMA. Winkelman and James18 determined the number C. Sweat artifact.
of 2-second bins during REM sleep that contained phasic D. A and C.
chin (defined as EMG activity lasting 0.15 seconds with an E. A and B.
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 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep 63

FIGURE 417

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin EMG

ECG

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin EMG

ECG

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin EMG

ECG
1 sec

Answers
2. B. Cool the patient down. Sweat artifact is shown. The
1. A. The electrode M1 is faulty because only derivations first step is to cool the patient down with a fan, reducing
containing M1 have the artifact (electrode popping). The the room temperature, or removing covers. Using a
scoring rules state that if an electrode in the recommended higher setting for the low-frequency filter (either 0.5 or
derivations is faulty, then the alternative derivations 1 Hz) would remove much of the undulation but will also
(F3-M2, C3-M2, O1-M2) should be used (see Chapter 1). reduce the size of genuine slow waves, thus reducing the
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64 Chapter 4 Biocalibration, Artifacts, and Common Variants of Sleep
amount of activity in the 0.5- to 2-Hz range meeting the
amplitude criteria for slow wave activity.
3. E. Both ECG and pulse artifact are noted. ECG artifact is
visible in all of the derivations. Pulse artifact is best seen
in F4-M1. Note the deflection follows the QRS and is
usually broader than deflections due to ECG artifact.
REFERENCES
1. Caraskadon MA, Rechschaffen A: Monitoring and staging
human sleep. In Kryger MH, Roth T, Dement WC (eds): Prin-
ciples and Practice of Sleep Medicine, 4th ed. Philadelphia: WB
Saunders, 2006, pp. 13591377.
2. Harris CD, Dexter D: Recording artifacts. In Shepard JW (ed):
Atlas of Sleep Medicine. Mount Kisco, NY: Futura, 1991,
pp. 5051.
3. Butkov N. Clinical Polysomnography. Ashland, OR: Synapse
Media, 1996, pp. 344346.
4. Berry RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley
& Belfus, 2003, pp. 5873.
5. White DP: Pathogenesis of obstructive and central sleep apnea.
Am J Respir Crit Care Med 2005;172:13631370.
6. Hauri P, Hawkins DR: Alpha-delta sleep. Electroenceph Clin
Neurophysiol 1973;34:233237.
7. Moldofsky H, Scarisbrick P, England R, Smythe H: Musculosk-
eletal symptoms and non-REM sleep disturbance in patients
with fibrositis syndrome and healthy subjects. Psychosom
Med 1975;37:341351.
8. Mahowald ML, Mahowald MW: Nighttime sleep and daytime
functioning (sleepiness and fatigue) in less well defined chronic
rheumatic disease with particular reference to alpha-delta
NREM sleep anomaly. Sleep Med 2000;1:195207.
9. Roizenblatt S, Moldofsky H, Benedito-Silva AA, Tufik S: Alpha
sleep characteristics in fibromyalgia. Arthritis Rheum 2001;
44:222230.
10. Johnson LC, Hanson K, Bickford RG: Effect of flurazepam on
sleep spindles and K complexes. Electroencephalogr Clin Neu-
rophysiol 1976;40:6777.
11. Johnson LC, Spinweber CL, Seidel WF, et al: Sleep spindle and
delta changes during chronic use of a short acting and a long
acting benzodiazepine hypnotic. Electroencephalogr Clin Neu-
rophysiol 1983;55:662667.
12. Obermeyer WH, Beneca RM: Effects of drugs on sleep. Neurol
Clin 1996;14:827840.
13. Schenck CH, Mahowald MW, Kim SW, et al: Prominent eye
movements during NREM sleep and REM sleep behavior dis-
order associated with fluoxetine treatment of obsessive-
compulsive disorder. Sleep 1992;15:226235.
14. Armitage R, Trivedi M, Rush AJ: Fluoxetine and oculomotor
activity during sleep in depressed patients. Neuropsychophar-
macology 1995;12:159165.
15. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring
of Sleep and Associated Events: Rules, Terminology and Tech-
nical Specifications, 1st ed. Westchester, IL: American Academy
of Sleep Medicine, 2007.
16. Silber MH, Ancoli-Israel S, Bonnet MH, et al: The visual
scoring of sleep in adults. J Clin Sleep Med 2007;15:121131.
17. American Academy of Sleep Medicine: International Classifi-
cation of Sleep Disorders, 2nd ed. Westchester, IL: AASM,
2005, pp. 148151.
18. Winkelman JW, James L: Serotonergic antidepressants are asso-
ciated with REM sleep without atonia. Sleep 2004;15:317321.
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Sleep Staging in Infants
and Children
Chapter Points
For infants younger than 2 months of age (48 wk
CAtime since conception), sleep may be staged
according to the rules of Anders, Emde, and Parmelee.
Sleep staging in infants depends on behavioral
observations because wake and sleep may have similar
EEG patterns.
In infants, AS corresponds to stage R and QS to NREM
sleep.
In term infants, entry to sleep via AS is the norm and
AS composes about 50% of sleep.
Timing of appearance of characteristic EEG patterns of
sleep (age postterm):
Sleep spindles 23 mo
K complex 46 mo
Slow wave activity 45 mo
By age 6 months, stages N1, N2, and N3 can usually be
scored (sometimes younger).
The DPR is the dominant rhythm over the occipital
regions in relaxed wakefulness with eyes closed. DPR is
attenuated by eye opening.
The frequency of the DPR increases with age. The
frequency of DPR increases from around 4 Hz at 4
months to 8 Hz by age 8 years in most individuals
(adult range 813 Hz).
Unique EEG patterns that are used to identify stage N1
in children include rhythmic anterior theta (57 Hz
over frontal derivation) and hypnagogic
hypersynchrony (high-voltage 34.5 Hz activity),
maximal in frontal and central derivations.
The American Academy of Sleep Medicine (AASM) scoring
manual1,2 provides new scoring rules for infants older than
2 months and children. However, previously, the terminol-
ogy for sleep staging for the newborn infant used different
terminology, and sleep was staged according to the sleep
scoring rules of Anders, Emde, and Parmelee.3 These have
been widely used for infants in the past and can still be
used for scoring sleep in infants younger than 2 months
Chapter 5
of age. The gestational age is the time from conception to
birth (estimated from last menstrual period). The concep-
tional age (CA) is gestational age + time in weeks since birth.
If one assumes term means 40 weeks, then the AASM rules
would apply at 48 weeks CA. For an infant born at 36 weeks,
the AASM rules would apply at age 3 months (CA 48 wk).
BIPOLAR ELECTROENCEPHOGRAM RECORDING
In some of the tracings to follow, bipolar electroencephalo-
gram (EEG) montages are illustrated using frontal (F3, F4, F7,
and F8), central (C3 and C4), parietal (P3, P4, P7, and P8), and
occipital (O1 and O2) electrodes (Fig. 51). Some of these
electrodes are used in standard sleep recording and others
are not. Clinical EEG is discussed in detail in Chapter 27.
However, for reference, EEG electrode positions are illus-
trated in Figure 51.
SLEEP IN THE PREMATURE INFANT AND
INFANTS YOUNGER THAN 48 WEEKS CA
Sleep Stages in the Newborn
Infant sleep is divided into active sleep (AS; corresponding
to rapid eye movement [REM] sleep), quiet sleep (QS; cor-
responding to nonrapid eye movement [NREM] sleep) and
indeterminant sleep, which is often a transitional sleep
stage. Unlike adults, infants transition from wake to sleep via
AS. The characteristics of each stage are listed in Table 51:
The EEG patterns associated with wake, QS, and AS are
discussed later.16 The sleep of premature infants differs from
that of term infants (CA 3840 wks). The timing of the
appearance of different EEG patterns characteristic of differ-
ent sleep stages is illustrated in Figure 52. Behavioral obser-
vations are essential for sleep staging because EEG patterns
may be associated with more than one state.
EEG Patterns
The EEG patterns of sleep in the pre-term and term
infant are3
1. Trac discontinue (TD): A discontinuous pattern consist-
ing of high-voltage bursts with sharp features separated
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66 Chapter 5 Sleep Staging in Infants and Children

by long, dramatically flat EEG periods of 10 to 20 seconds 3. Low-voltage irregular (LVI): Continuous low-voltage
(Fig. 53). TD is seen at or before 30 weeks CA (see Fig. mixed-frequency with prominent delta and theta rhythms
52) and is the EEG pattern of QS in that age group. and little variation. Voltage (1435 V), theta rhythm
2. Trac alternant (TA): A discontinuous pattern (Figs. 54 predominates (see Fig. 54).
and 55) that characterizes the QS of newborns after 4. High-voltage slow (HVS) pattern: Continuous, irregular
about 30 weeks CA (see Fig. 52). Bursts of mixed activity mixed frequencies with higher voltages (50100 V) and
of 2 to 8 seconds are interspersed with periods of flatter more prominent delta frequencies (see Fig. 54).
EEG. The bursts are composed of high-voltage slow waves 5. Mixed pattern (M): Similar to LVI but with slightly higher
superimposed with rapid low-voltage sharp waves. There voltages and more delta activity. Mixture of HVS and low-
is a continuum between TD and TA, but in general, in voltage polyrhythmic activity (see Fig. 54).
TA, the high and low periods have fairly equal durations
and the bursts do not have full bilateral synchrony. In TD,
Premature Infants
the flat is very flat and the bursts are very high voltage
and have synchrony. In premature infants with a CA less than 30 weeks, QS
usually shows a pattern of TD.3,4 The pattern of TD is
characterized by electrical quiescence between bursts of
high-voltage activity. In contrast, TA is characterized by a
lesser reduction in amplitude between periods of higher-
amplitude activity. Another difference between TA and TD
is that delta brushes (fast waves of 1020 Hz) are superim-
Fp1 Fp2 posed on the delta waves in TD. As the infant matures, delta
brushes disappear and the TA pattern replaces TD. Finally,
F7 F8
Fz at term, the EEG of QS is characterized by an HVS pattern.
F3 F4
The EEG of AS in premature infants younger than 30 weeks
may also show TD but later is typically LVI or M. The
T7 C3 Cz C4 T8 EEG pattern of wake and sleep is similar and states are dis-
tinguished by sustained eye closure (sleep) and open eyes
(wake).
P3 Pz P6
P7 P8
Term Infants
O1 O2 Wakefulness is characterized by crying, open eyes, and
feeding. Non-nutritive sucking commonly continues during
sleep. Sleep is often defined by sustained eye closure. The
FIGURE 51 Electroencephalography (EEG) electrode positions. C = central; F = epochs during the transition from definite AS to QS are often
frontal; Fp = frontopolar; O = occipital; P = parietal; T = temporal. scored as indeterminant sleep.

TABLE 51
Characteristics of Sleep Stages in Term Infants3
WAKE ACTIVE SLEEP QUIET SLEEP INDETERMINANT
EEG LVI or mixed LVI TA or HVS Not meeting criteria
M, HVS rarely M rarely for QS or AS
Premature: TD
EOG Eyes open Eyes closed, horizontal REMs Eyes closed
Little or none
Chin Phasic Low tonic between movements High tonic
Breathing Irregular Irregular, some postsigh pauses Regular
Deep and slow
Body Calm or active Squirming, sucking, grimacing Few, peaceful
movements with eyes open Body: small digit or limb movements Sucking can occur
AS = active sleep; EEG = electroencephalogram; EOG = electromyography; HVS = high-voltage slow; LVI = low-voltage irregular; M = mixed; QS = quiet sleep;
REMs = rapid eye movements; TA = trac alternant; TD = trac discontinue.
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 Chapter 5 Sleep Staging in Infants and Children 67

POST CONCEPTIONAL AGE IN WEEKS FIGURE 52 Appearance of different EEG patterns by conceptional age
24 26 28 30 32 34 36 38 40 42 44 46 48 50 in weeks. HVS = high-voltage slow; LVI = low-voltage irregular; M =
mixed; TA trac alternant; TD = trac discontinue. The dark bars refer to
Active sleep TD LVI or M discontinuous patterns. Examples of these patterns are illustrated in
Figures 53 to 56. From Libenson MH: Practical Approach to
Wakefulness TD LVI or M Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 321.

Quiet sleep TD TA HVS

Saw tooth waves

Delta brushes

Sharp transients

Sleep spindles

Vertex waves

Discontinuous Continuous

100 V
1 sec
LUE-RAE
ECG
Chin
Resp

Fp1-T7
T7-O1

Fp1-C3
C3-O1

Fp2-C4
C4-O2

Fp2-T8
T8-O2

T7-C3
C3-Cz
Cz-C4
C4-T8

FIGURE 53 Trac discontinue. Bursts of high-voltage activity alternate with long periods of flat EEG activity. ECG = electrocardiogram; LUE = left under eye electrode; RAE = right
above eye electrode. From Libenson MH: Practical Approach to Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 307.

AS is characterized by grimacing, sucking, an LVI EEG

pattern, REMs, and low electromyogram (EMG) activity
(Fig. 56; see also Table 51). Breathing is irregular in AS.
QS (Fig. 57) is characterized by a peaceful infant with non-
nutritive sucking and regular deep respiration. The EEG may
show TA at early ages and HVS later. No or few eye move-
ments are noted and the chin EMG is tonic and high.
Sleep Architecture
Newborn infants typically have periods of sleep lasting 3 to
4 hours interrupted by feeding, and the total sleep duration
in 24 hours is usually 16 to 18 hours. They have cycles of
sleep with a 45- to 60-minute periodicity with about 50% AS.
In newborns, the presence of REM (AS) at sleep onset is the
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68 Chapter 5 Sleep Staging in Infants and Children

FIGURE 54 EEG patterns of the newborn infant (30 sec tracings).

HVS = high-voltage slow; LVI = low-voltage irregular; M = mixed. 50 V
Reproduced with permission from Anders T, Emde R, Parmelee A: A LVI
Manual of Standardized Terminology, Techniques and Criteria for
Scoring of Stages of Sleep and Wakefulness in Newborn Infants. Los
Angeles: Brain Information Service, UCLA, 1971. M

HVS

Trac alternant
(TA)

70 V
Resp
1 sec
Eyes
ECG

Fp1-F7
F7-T7
T7-P7
P7-O1

Fp1-F3
F3-C3
C3-P3
P3-O1

Fz-Cz
Cz-Pz

Fp2-F4
F4-C4
C4-P4
P4-O2

Fp2-F8
F8-T8
T8-P8
P8-O2

FIGURE 55 Trac alternant (TA; quiet sleep in a 1-mo-old). Note that the quiet portions are not as flat or as long as in trac discontinue (TD). Also, the higher-amplitude burst
portions are longer and less synchronous. ECG = electrocardiogram. From Libenson MH: Practical Approach to Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 308.

norm. In contrast, the adult sleep cycle is 90 to 100 minutes,
REM occupies about 20% of sleep, and NREM sleep is noted
at sleep onset.
After about 3 months, the percentage of REM sleep starts
to diminish and the intensity of body movements during AS
(REM) begin to decrease. The pattern of NREM at sleep
onset begins to emerge. However, the sleep cycle period
does not reach the adult value of 90 to 100 minutes until
adolescence.712
As children mature, more typical adult EEG patterns
begin to appear. The time of appearance is somewhat
variable, but the values in Table 52 are typical. Sleep
architecture in children is discussed in more detail in
Chapter 6.
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 Chapter 5 Sleep Staging in Infants and Children 69

200 V
1 sec
Resp

Eyes
ECG
Chin
Fp1-F7
F7-T7
T7-P7
P7-O1

Fp1-F3
F3-C3
C3-P3
P3-O1

Fz-Cz
Cz-Pz

Fp2-F4
F4-C4
C4-P4
P4-O2

Fp2-F8
F8-T8
T8-P8
P8-O2

FIGURE 56 Active sleep. The EEG shows an LVI pattern. The respiration channel shows irregular respiration with a respiratory pause. The eye movement channel shows rapid eye
movements. ECG = electrocardiogram. Adapted from Libenson MH: Practical Approach to Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 310.

70 V
1 sec Fp1-F7
F7-T7
T7-P7
P7-O1

Fp1-F3
F3-C3
C3-P3
P3-O1

Fz-Cz
Cz-Pz

Fp2-F4
F4-C4
C4-P4
P4-O2

Fp2-F8
F8-T8
T8-P8
P8-O2

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FIGURE 57 Quiet sleep showing an HVS EEG pattern in a term infant. From Libenson MH: Practical Approach to Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 306.
70 Chapter 5 Sleep Staging in Infants and Children

TABLE 5-2 comprising more than 20% of the duration of epochs,

Age of Onset of Electroencephalographic Patterns score as stage N (NREM).
C. If some epochs of NREM sleep contain greater than
WAVE FORM DESCRIPTION AGE FIRST SEEN
20% SWA, score these as stage N3 (NREM 3). If the
Sleep spindles 1216 Hz 23 mo remaining NREM epochs contain no K complexes or
K complexes Biphasic initial neg 46 mo spindles, score as stage N (NREM).
(up) D. If NREM is sufficiently developed that some epochs
Deflection contain sleep spindles and K complexes and other
Slow wave >75 V p-p in 45 mo epochs contain sufficient amounts of SWA, score
activity frontal derivation postterm NREM sleep in the infant as either stage N1, N3, or
Frequency 0.52 Hz N3 as in an older child or adult.
p-p = peak-to-peak.
Notes:

1. Behavioral correlates are important in children 6

months postterm or younger.
SCORING SLEEP IN INFANTS OLDER 2. NREM is characterized by regular respiration, no or
THAN 48 WEEKS CA AND CHILDREN rare vertical eye movements, and preserved EMG tone.
3. REM is characterized by irregular respiration, chin
AASM Pediatric Rules for Scoring Sleep
EMG atonia, and REMs.
Ages for which AASM Pediatric Sleep 4. Spontaneous eye closure in an infant indicates
Scoring Rules Apply drowsiness.
A. Pediatric sleep scoring rules can be used to score sleep 5. By age 6 months (and sometimes younger), stages
and wakefulness in children 2 months postterm or older.2 N1, N2, and N3 can usually be scored.

Postterm means at least 40 weeks after conception
(2 mo postterm = 48 wk CA). For example, for an
infant born at 36 weeks postconception, the scoring
rules apply 3 months after birth.
For children younger than 2 months postterm, the
AASM scoring manual refers the reader to the Pediatric
Task Force review paper.1 The scoring rules of Anders,
Emde, and Parmelee can be used.
There is no precise upper age limit for pediatric rules.
Terminology of Sleep Stages
A. The following terminology should be used when scoring
sleep in children 2 months postterm or older:
1. Stage W (wakefulness)
2. Stage N1 (NREM 1)
3. Stage N2 (NREM 2)
4. Stage N3 (NREM 3)
5. Stage N (NREM)
6. Stage R (REM)
Scoring Sleep Stage
In the scoring of infant sleep, four possible scenarios are
described:
A. If all epochs of NREM sleep contain no recognizable
sleep spindles, K complexes, or high-amplitude 0.5- to
2-Hz slow wave activity (SWA), score all epochs of
NREM sleep as stage N (NREM).
B. If some epochs of NREM sleep contain sleep spindles
or K complexes, score those as stage N2 (NREM 2). If
the remaining NREM epoch contains no SWA
Figure 58 presents an example of a 3-month-old infant
who had SWA but no definite sleep spindles or K complexes.
NREM sleep was scored either stage N3 (epochs meeting
criteria for stage N3) or stage N.
Dominant Posterior Rhythm
Dominant posterior rhythm (DPR) in both adults and chil-
dren is defined as the predominant rhythm seen over occipi-
tal derivations during eyes closed wakefulness that is
reactive. (Reactive = activity blocks or attenuates with eye
opening and appears with passive eye closure.)
The DPR in adults is often called alpha rhythm and
consists of activity most prominent over occipital derivations
with an amplitude of less than 50 V and a frequency of
8.5 to 13 Hz; it is reactive to eye opening (decreased
amplitude).
Of note, 10% to 25% of adults have no or poorly defined
alpha rhythm.
The DPR in infants and children changes with age.
Table 53 shows the characteristic changes. A simple rule to
remember is greater than 8 by age 8, meaning that in
normal awake children older than age 8, the DPR is greater
than 8 Hz (813 Hz).
Additional Waveforms of Wakefulness
1. Posterior slow waves (PSWs) of youth: This waveform
occurs in children between 8 and 14 years and has a fre-
quency of 2.5 to 4.5 Hz. PSW usually occurs at the same
time as DPR with eyes closed wake and disappears with
drowsiness or transition to stage N1 sleep. Maximal inci-
dence is 8 to 14 years of age, rare younger than 2 years or
older than 211 (Fig. 59).
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 Chapter 5 Sleep Staging in Infants and Children 71

200 V
1 sec F4-M1
C4-M1
O2-M1
E2-M2
E1-M2
Chin
A

F4-M1
C4-M1
O2-M1
E2-M2
E1-M2
Chin

FIGURE 58 This 3-month-old infant had no sleep spindles or K complexes but had slow wave activity (nonrapid eye movement N3 [NREM 3]) and epochs of rapid eye movement
(REM) sleep. This case shows stage N3 (A) and stage R (B).

TABLE 53
Dominant Posterior Rhythm Characteristics by Age
FREQUENCY % OF CHILDREN SHOWING AMPLITUDE
(HZ) THE PATTERN AT THIS AGE (V) WAVEFORM DISTRIBUTION
<34 mo Slow 100 Not used Irregular Occipital
34 mo 3.54.5 75 50100 Sinusoidal Occipital
56 mo 56 70 by 12 mo 50110 Sinusoidal Occipital
3 yr 7.59.5 82 Sinusoidal Occipital
69 yr 813 ~88 Average Sinusoidal Occipital
5060
>9 yr 813 90 Not used Sinusoidal Occipital
Memory tool: 4 Hz at 4 mo and 8 Hz at 8 yr.

POSTERIOR SLOW WAVES OF YOUTH

Maximal incidence 8 to 14 years of age

P3-O1

A 50 V
1 sec

FIGURE 59 A, Posterior slow waves (PSWs) of youth in an occipital derivation. Alpha waves are superimposed on slow waves. B,
Underlying slow wave activity. PSW is present only with eyes closed and disappears with drowsiness and sleep. PSW is a pattern of
relaxed wakefulness.
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72 Chapter 5 Sleep Staging in Infants and Children

2. Blinks: Eye blinks in children, as in adults, are associated
with the eyeball turning upward (Bells phenomenon). In
children, they cause occipital sharp waves that are mono-
phasic or biphasic (200400 msec) and less than 200 V
that follow eye blinks.
3. Slow eye movements (SEMs) or REMs are defined the
same as in adults.
Pediatric Stage W Rules2
A. DPR in children is the same as alpha in adults for scoring
sleep and wake.
B. Score stage W when age-appropriate DPR or alpha occu-
pies more than 50% of the epoch over the occipital
region.
C. If there is no discernible reactive alpha or no age-
appropriate DPR, score stage W when either of these is
present (Table 54):
1. Eye blinks at a frequency of 0.5 to 2 Hz.
2. Reading eye movements.
3. Irregular conjugate REM associated with normal or
high chin muscle tone.
Waveforms for Scoring Pediatric Stage N12
In staging N1, the presence or absence of certain waveforms
is important (Table 55).
TABLE 5-4
Pediatric Stage W Rules1,2
A. If there is alpha rhythm or age-appropriate DPR
1. Score wake if alpha/DPR is present for more than 50%
of the epoch.
B. If there is no alpha or DPR, score wake when
1. Eye blinks are present.
2. Reading eye movements are present.
3. There are rapid eye movements with normal or high
EMG tone.
DPR = dominant posterior rhythm; EMG = electromyography.
1. Rhythmic anterior theta (RAT) activity consists of runs
of moderate voltage, 5- to 7-Hz, activity largest over the
frontal regions. RAT activity is common in adolescents
and young adults during drowsiness and first appears
around 5 years of age1,5 (Figs. 510 and 511).
2. Hypnagogic hypersynchrony (HH) is characterized by
bursts of very high amplitude 3- to 4.5-Hz sinusoidal
waves maximal in frontal and central derivations and
smallest in the occipital derivation (widely distributed)
(see Fig. 510).
3. Low-amplitude mixed-frequency (LAMF): Low-
amplitude, predominantly 4- to 7-Hz activity.
4. Vertex sharp waves are sharply contoured waves with
duration less than 0.5 second maximal over the central
region and distinguishable from background activity.
5. SEMs: Conjugate, reasonably regular, sinusoidal eye
movements with initial deflection that last longer than
500 msec.
Pediatric Stage N1 Rules2
A. If alpha/DPR is generated, score stage N1 if the posterior
rhythm is attenuated or replaced by LAMF activity for
more than 50% of the epoch (Fig. 512 and Table 56).
B. If alpha/DPR is not generated, score stage N1 com-
mencing with the earliest of any of the following
phenomena:
1. Activity in range 4 to 7 Hz with slowing of back-
ground frequencies by 1 to 2 Hz or higher from stage
W (e.g., 5 Hz and stage W had 7 Hz).
2. SEMs.
3. Vertex sharp wave.
4. RAT activity.
5. HH.
6. Diffuse or occipital predominant high-amplitude
rhythmic 3- to 5-Hz activity.
Pediatric Stage N2
Score as per adult rules:
Sleep spindles in children differ somewhat from those in
adults. In infants, sleep spindles are often asynchronous until

TABLE 55
Waveforms Important for Scoring Pediatric Stage N11,2
FREQUENCY/DURATION DISTRIBUTION AMPLITUDE AGE OF ONSET
LAMF 47 Hz All regions Low
Vertex sharp <0.5 sec (usually Central, vertex Stands out from 23 mo (broad)
waves <200 msec) background 5 mo (adult-like)
RAT activity 57 Hz Frontal regions Not a criteria Starts around age 5 yr
generally low Common in children
and adolescents
Hypnagogic 34.5 Hz Frontal and Very large Appears around 3 mo
hypersynchrony central 75350 V Common 68 yr
Rare > 12 yr
LAMF = low-amplitude mixed-frequency; RAT = rhythmic anterior theta.
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 Chapter 5 Sleep Staging in Infants and Children 73

200 V
1 sec

F4-M1

F3-M2

C4-M1

C3-M2

O2-M1

O1-M2

E1-M2

E2-M2

Chin

A B

FIGURE 510 A, Hypnagogic hypersynchrony (HH). High-voltage bursts, frequently 3 to 4 Hz, are prominent in frontal and central derivations.
B, Rhythmic anterior theta is faster than HH at 5 to 7 Hz and prominent in frontal derivations.

50 V
1 sec
F7-F3
F3-Fz
Fz-F4
F4-F8
A1-T3
T7-C3
C3-Cz
Cz-C4
C4-T8
T8-A2
P7-P3
P3-Pz
Pz-P4
P4-P8
Fz-Cz
Cz-Pz

FIGURE 511 Rhythmic anterior theta in a 12-year-old child during drowsiness (considered stage N1). From Neidermeyer E, Da Silva
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FL: Encephalography, Clinical Applications and Related Fields, 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2005, p. 227.
74 Chapter 5 Sleep Staging in Infants and Children

1 sec

O2-M1

FIGURE 512 The dominant posterior rhythm slows from 4 to 4.5 Hz to 3 Hz in a 4-month-old during transition from stage W to stage N1.

FIGURE 513 Asynchronous sleep spindles

in a 6-month-old girl. In the first part of the
tracing, spindles are seen on the right (F4-C4)
Fp1-F3
but not on the left. In the second part of the
tracing, sleep spindles are seen on the left
F3-C3
(F3-C3) but not on the right. From Tyner FS,
Knott JR, Mayer WB: Fundamentals of EEG
Technology. New York: Raven, 1982, p. 243. C3-P3

P3-O1

Fp2-F4

F4-C4
100 V
1 sec
C4-P4

P4-O2
60 mo. HF  70 LF  1

TABLE 5-6 Frontal spindles typically are 11 to 12.5 Hz compared

Pediatric N1 Scoring Rules2 with 12.5 to 14.5 Hz in centroparietal regions.
Score stage N1 Centroparietal spindles show little change with age 4 to
In subjects who generate DPR 24 years, whereas frontal spindles decreased dramatically in
DPR is attenuated or replaced by LAMF for > 50% of power and became stable about age 13.1
the epoch.
Pediatric Stage N3
In subjects who do NOT generate DPR
Score N1 beginning with the earliest of any of the Score as per adult rules (Table 57).
following phenomenon: SWA for sleep staging is defined as greater than 75 V
Slowing of background frequencies > 12 Hz from peak to peak in the frontal derivation with a frequency of
those of stage W. 0.5 to 2 Hz (20.5-sec width). Slow waves in children are
Slow eye movements. often 100 to 400 V (Fig. 516; see also Fig. 515). Slow
Vertex sharp waves. waves appear as early as 3 months but more often about 3 to
RAT activity. 4.5 months postterm. In scoring adult sleep, the major ques-
Hypnagogic hypersynchrony. tion for epochs containing low-frequency activity: is the
Diffuse or occipital predominant high-amplitude amplitude criteria met for at least 6 seconds? In children,
rhythmic 3- to 5-Hz activity. the major decision is what constitutes slow activity because
DPR = dominant posterior rhythm; LAMF = low-amplitude mixed-frequency; nearly all activity exceeds 75 V peak to peak.
RAT = rhythmic anterior theta.
Pediatric Stage R
Score as per adult rules.
age 1 to 2 years. Figure 513 illustrates an example of asyn-
The stage R of pediatric sleep differs from adults only in
chronous spindles.1,6
that the background activity may not look as familiar
Sleep spindles in children:
(Table 58). The background rhythm varies somewhat and
can have some SWA (see Fig. 58B).
Sleep spindles occur independently at two different
locations and frequencies in children and adolescents Pediatric Arousal Rules
(Figs. 514 and 515; see also Fig. 513). Same as for adults.
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 Chapter 5 Sleep Staging in Infants and Children 75

200 V
1 sec SS
F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin

FIGURE 514 Stage N2 in a 5-year-old boy. Note the sleep spindle most prominent in the frontal derivation. In adults, sleep spindles are most prominent in central
derivations. There are also bursts of theta activity (hypnagogic hypersynchrony).

200 V

1 sec

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin

FIGURE 515 Stage N3 (30 second epoch). The patient is a 5-year-old boy. The horizontal amplitude lines in the derivation F4-M1 are 75 V apart. The dark bars
above F4-M1 show slow wave activity that exceeds 6 seconds in a 30-second epoch.

TABLE 5-7 TABLE 58

Pediatric Stage N3 Scoring Rules2 REM Sleep in Children: Background Activity1,2
Score stage N3 BACKGROUND ACTIVITY DURING
Criteria: SWA (20% of epoch [6 sec]). SWA > 75 V AGE REM SLEEP
peak-to-peak in frontal derivation and frequency
7 wk postterm 3 Hz
0.52 Hz.
Sleep spindles may or may not be present. 5 mo 45 Hz saw-tooth waves at 5 mo
Usually no eye movements in stage N3.
9 mo 46 Hz
Chin EMG is variable and not part of the scoring criteria.
EMG = electromyogram; SWA = slow wave activity. 15 yr 57 Hz activity
510 yr As adults
REM = rapid eye movement.
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76 Chapter 5 Sleep Staging in Infants and Children

200 V
1 sec

F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin

FIGURE 516 Stage N3 in a 5-month-old boy. The horizontal amplitude lines in F4-M1 are 75 V apart.

CLINICAL REVIEW QUESTIONS 6. Which of the following is true about HH?

1. The sleep scoring rules of Anders, Emde, and Parmelee A. An important waveform for scoring stage N1.
may be used for infants younger than what age? B. The frequent range is typically 4 to 7 Hz.
A. 3 months of age (term infant). C. Most prominent over occipital area.
B. 48 weeks conceptual age. D. Moderate amplitude.
C. 1 month post term. 7. At what age do sleep spindles typically appear?
D. 6 months of age. A. 4 months.
2. Which of the following is NOT true about the sleep of an B. 23 months.
infant 1 month post term? C. 6 months.
A. Usually enters sleep via AS. D. 8 months.
B. Active sleep accounts for 30% of the total sleep
8. By what age can stage N1, N2, and N3 typically be scored?
time.
A. 2 months.
C. Grimacing and small digit and limb movements are
normal in AS. B. 4 months.
D. Breathing is regular in QS. C. 6 months.
D. 1 year.
3. What is the typical total sleep time and duration of the
sleep cycle in term infants?
A. 20 hours, 60 minutes. Answers
B. 16 hours, 90 minutes.
1. B. 48 weeks conceptual age (equivalent to 2 mo post
C. 16 hours, 45 minutes. term).
D. 20 hours, 30 minutes.
2. B. AS accounts for around 50% of the total sleep time in
4. What is true about the DPR in young children? a term infant.
A. Increased with eye closure, attenuated with eye
opening. 3. C. Total sleep time is 16 to 18 hours and sleep cycle is
about 45 minutes.
B. Most prominent in central derivations.
C. Score stage N1 if more than 50% of the epoch mani- 4. A. DPR reaches 8 Hz around 8 years of age and is most
fests the DPR. prominent in occipital derivations. Score stage W if more
D. DPR reaches the 8-Hz range at about 12 years of age. than 50% of the epoch manifests DPR.

5. Posterior slow waves of youth occur in which sleep 5. D. Posterior slow waves of youth occur during eyes-
stage? closed wake and vanish with sleep onset.
A. Stage N3.
6. A. HH is important for staging N1 in children. The fre-
B. Stage N1. quency is usually 3 to 4.5 Hz and the waveform has a high
C. Stage N2. amplitude most prominent in frontal and central areas
D. Stage W. and smallest in occipital regions.
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7. B. Sleep spindles typically appear at 2 to 3 months of age.
8. C. Stage N1, N2, and N3 can typically be scored by 6
months of age (and sometimes sooner).
REFERENCES
1. Grigg-Damberger M, Gozal D, Marcus CL, et al: The visual
scoring of sleep and arousal in infants and children. J Clin Sleep
Med 2007;3:201240.
2. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring
of Sleep and Associated Events: Rules, Terminology and Tech-
nical Specifications, 1st ed. Westchester, IL: American Academy
of Sleep Medicine, 2007.
3. Anders T, Emde R, Parmelee A: A Manual of Standardized
Terminology, Techniques and Criteria for Scoring of Stages of
Sleep and Wakefulness in Newborn Infants. Los Angeles: Brain
Information Service, UCLA, 1971.
4. Libenson MH: Practical Approach to Electroencephalography.
Philadelphia: Elsevier Saunders, 2010, p. 321.
Chapter 5 Sleep Staging in Infants and Children 77
5. Neidermeyer E, Da Silva FL: Encephalography, Clinical Appli-
cations and Related Fields, 5th ed. Philadelphia: Lippincott
Williams & Wilkins, 2005, p. 227.
6. Tyner FS, Knott JR, Mayer WB: Fundamentals of EEG Technol-
ogy. New York: Raven, 1982, p. 243.
7. Kahn A, Dan B, Grosswasser J, et al: Normal sleep architecture
in infants and children. J Clin Neurophysiol 1996;13:184297.
8. Seldon S: Polysomnography in infants and children. In Sheldon
SH, Ferber R, Kryger MH (eds): Principles and Practice of
Pediatric Sleep Medicine. Philadelphia: Elsevier Saunders,
2005, pp. 4971.
9. Iglowstein I, Jenni OG, Molinari L, Largo RH: Sleep duration
from infancy to adolescense: reference values and generational
trends. Pediatrics 2003;111:302307.
10. Montgomery-Downs HE, OBrien LM, Gulliver TE, et al: Poly-
somnographic characteristics in normal preschool children.
Pediatrics 2006;117:741753.
11. Mason TB, Teoh L, Calabro K, et al: Rapid eye movement latency
in children and adolescence. Pediatr Neurol 2008;39:162169.
12. Beck SE, Marcus CL: Pediatric polysomnography. Sleep Med
Clin 2009;4:393406.
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Sleep Architecture Parameters,
Normal Sleep, and Sleep Loss
Chapter Points
Sleep in adults is characterized by 3 to 5 cycles of NREM/
REM sleep, each lasting about 90 to 100 minutes.
The duration of stage R in each cycle is typically longer
in the second part of the night. The individual
episodes of REM are also longer. The REM density (eye
movements/time) is greater in the second part of the
night.
Most stage N3 occurs in the first part of the night.
In adults, the TST and sleep efficiency decrease and
the amount of wake increases with age. There is also a
modest increase in the sleep latency and a decrease in
the REM latency.
In men, the amount of stage N3 decreases with age
and the amount of stage N1 increases. In women, the
amount of stage N3 does not decrease with age.
In adults, the amount of stage R decreases slightly with
age.
The normal ArI increases with age.
A number of medications increase the REM latency
including selective serotonin reuptake inhibitors,
tricyclic antidepressants, and lithium.
Infants commonly enter sleep via stage R (or active
sleep) and have a sleep cycle (4560 min) that is much
shorter than that of adults.
After sleep deprivation, recovery sleep is usually
characterized by an increase in stage N3 on the first
recovery night with an increase in REM sleep on
subsequent nights.
Chronic sleep restriction can have a number of adverse
health consequences. These include a reduction in
leptin, an increase in ghrelin, and impaired glucose
metabolism.
A number of parameters concerning the quantity and quality
of sleep are usually included in polysomnography (PSG)
reports1,2 (Table 61). Typically, PSG data recording starts
before lights out to verify that the electrodes and monitoring
equipment are providing adequate signals. In addition, cali-
brations and biocalibrations are recorded as described in
Chapter 4. Lights out time is the time at which the patient
is allowed to fall asleep and marks the start of data that will
Chapter 6
be staged and analyzed. Lights on is the time that recording
of sleep is terminated. Total recording time (TRT) is the
time from lights out to lights on. Some sleep centers also
record another set of biocalibrations after lights on. The
sleep latency is the time from lights out to the start of the
first epoch of sleep. Wake after sleep onset (WASO) as
defined by the American Academy of Sleep Medicine
(AASM) scoring manual includes all stage W after sleep
onset (from the start of the first epoch of sleep) until lights on.
It also includes out-of-bed wake time during the period from
sleep onset until lights on. The total amount of stage W
(during TRT) = sleep latency + WASO.
Previously, some clinicians used the term sleep period
time (SPT), defined as the time from sleep onset to the final
awakening. WASO was then defined as the duration of wake
during the sleep period time (WASOSPT). That is, WASOSPT
= SPT TST, where TST = total sleep time. The AASM
scoring manual has standardized the definition of WASO
and does not use the SPT as a standard parameter. However,
a considerable number of publications3 previously used SPT
and WASOSPT (formerly identified as WASO), so the reader
should be familiar with this terminology. The AASM scoring
manual also recommends presentation of the durations of
the sleep stages both as an absolute duration and as a per-
centage of TST. Some authors previously presented WASOSPT
and the sleep stages as a percentage of SPT.
NORMAL SLEEP IN ADULTS
Sleep occurs in cycles, each usually composed of a period of
nonrapid eye movement (NREM) sleep followed by stage
R rapid eye movement (REM) sleep. There are usually three
to five NREM/REM cycles per night (Table 62). A useful
approach for presentation of sleep cycle data is the hypno-
gram. This is a plot of sleep stage versus time of night
(Fig. 61). Although the sleep architecture parameters listed
previously are useful, they obviously do not provide details
about the pattern of sleep over the night. Hypnograms can
be very informative, and many sleep centers include a hyp-
nogram in their sleep report.
Sleep architecture is a term used to denote the structure
of sleep. In young adults, stage N1 usually occupies approxi-
mately 5% to 10% of the TST.35 It is a transitional state
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79
80 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss

TABLE 61
Sleep Architecture Parameters
TRT (min) Time duration from lights out to lights on.
TRT = SL + WASO + TST
Lights out time (hr : min) Time of the start of the recording.
Lights on time (hr : min) Time of the end of the recording.
TRT (min) Time from lights off to lights on.
TST (min) Time spent in stages N1, N2, N3, and R.
SL (min) Time from lights out until the start of the first epoch of sleep (stages N1, N2, N3, or R).
Stage R latency (min) (REM latency) Time from start of first epoch of sleep until the start of the first epoch of stage R.
Sleep efficiency (%) = TST 100/TRT.
Stage W (min) All minutes of stage W during TRT.
WASO Stage W recorded after sleep onset until lights on time.
= stage W SL
Time in each sleep stage (min) Minutes of stages N1, N2, N3, R.
Time in each sleep stage as a % of TST Minutes of each sleep stage 100/TST.
Arousal (number) Total number of arousals.
ArI (#/hr) Total number of arousals 60/TST (min).
ArI = arousal index; REM = rapid eye movement; SL = sleep latency; TRT = total recording time; TST = total sleep time; WASO = wake after sleep onset.
After Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specifications, 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.

TABLE 62 Hypnogram 1 Stage R (REM)

Sleep Architecture Facts
W
35 sleep (NREM REM) cycles during the night
Sleep stage

R
Stage N3 N1
Most stage N3 is during the first half of the night
N2
Delta power decreases with each NREM cycle
N3
Stage R A B C
Episodes of stage R are longer in the second part of 23 24 1 2 3 4 5 6 7 8
the night Time
REM density (number of eye movements per time
during REM sleep) is higher in later episodes of REM Hypnogram 2
sleep
NREM = nonrapid eye movement; REM = rapid eye movement. W
Sleep stage

R
N1
N2
between wake and the other stages of sleep. Stage N2 occu-
pies the greatest proportion of the TST and accounts for N3
A B
approximately 50% to 60% of sleep. Stage N3 occupies
approximately 15% to 20% of the TST and stage R approxi- 23 24 1 2 3 4 5 6 7 8
Time
mately 20% of the TST. The amplitude of the slow waves and
amount of stage N3 is greatest in the first sleep cycle (see Fig. FIGURE 61 Hypnograms. Hypnogram 1 is from a normal individual. Hypnogram 2 is
61). Using spectral analysis, one can compute the delta from a patient complaining of frequent nocturnal awakenings. The first rapid eye
power (the contribution of slow wave activity to the total movement (REM) period is missed and there is a long REM latency. There are frequent
electroencephalogram [EEG] activity) (Fig. 62). The delta awakenings during the night.
power is highest during the initial cycle of NREM sleep. The
episodes of stage R occur about every 90 to 120 minutes, and
they are of longer duration as the night progresses. The REM
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 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss 81

TABLE 63
Stages in Sleep Architecture with Aging (2060 yr)
Delta power

INCREASE WITH DECREASE

AGE WITH AGE
Changes Sleep latency Stage N3 (%TST)5
with aging WASO (most change Stage N3 (%TST)
(2060 yr) after 40 yr) men only6
Stage N1 (%TST)5 Stage R (%TST)5,6
NREM REM Stage N1 (%TST) REM latency
Time of night men only6
Stage N2 (%TST)5 TST
FIGURE 62 Schematic illustrating the fact that delta power (amount of slow wave Stage N2 (%TST) Sleep efficiency
activity) decreases with subsequent episodes of nonrapid eye movement (NREM) men only6
sleep. Note delta power is very low during episodes of rapid eye movement (REM) sleep. REM = rapid eye movement; TST = total sleep time; WASO = wake after sleep
onset.

TABLE 64
Change in Sleep Architecture with Age (Sleep Heart Health Study)*
AGE RANGE
QUARTILE 1 QUARTILE 2 QUARTILE 3 QUARTILE 4
STAGE SEX (3754 YR) (5560 YR) (6170 YR) (>70 YR)
Stage N1 Men 5.8 6.3 7.1 7.6
Women 4.6 5.0 5.0 4.9
Stage N2 Men 61.4 64.5 65.2 66.5
Women 58.5 56.2 57.3 57.1
Stage N3 Men 11.2 8.2 6.7 5.5
Women 14.2 17.0 16.7 17.2
Stage R Men 19.5 19.1 18.4 17.8
Women 20.9 20.2 19.3 18.8
*Stage as a % of TST in four age quartiles.
TST = total sleep time.
From Redline S, Kirchner L, Quan SF, et al: The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture. Arch Intern Med 2004;164:406418.

density is the number of eye movements per time. The REM
density tends to be the highest in the later REM periods. In
fact, the initial REM period of the night is often difficult to
score owing to infrequent REMs. The first REM period also
may have K complexes or sleep spindles in epochs with both
low chin electromyogram (EMG) and REMs. According to
the AASM scoring manual, such epochs are scored as stage
R1 (see Chapter 3). During the last half of the night, most
sleep is composed of stage N2 and stage R with intervening
stage W and stage N1. Figure 61A presents a normal hyp-
nogram. Figure 61B shows a hypnogram with a longer sleep
latency, a long REM latency, two episodes of stage N3 sleep,
and more stage W.
CHANGES IN SLEEP ARCHITECTURE WITH
AGING (ADULTS)
Sleep architecture changes as adults grow older (Table 63).46
In general, sleep becomes lighter and more fragmented. There
is an increase in the sleep latency, WASO, and stages N1 and
N2.5 One study found an increase in stages N1 and N2 in
men only.6 There is a decrease in stage N3 (men only) and a
small decrease in stage R. The REM latency decreases with
age. Study of sleep architecture in older adults is complicated
by inclusion of individuals with medical or mental disorders
in some studies of the effect of aging on sleep architecture.
Many early studies did not include a sufficient number of
women. Ohayon and coworkers5 performed a large meta-
analysis of sleep architecture and attempted to specify normal
values with and without exclusion of patients with mental
diseases that could alter sleep architecture. Redline and col-
leagues6 have published another analysis of the effect of age
on sleep architecture (Sleep Heart Health Study). They
studied a large group of patients using standardized recording
and scoring techniques (Table 64). This study evaluated
information from sleep studies of patients 37 years and older
and divided the study group into four age quartiles. The sleep
studies were performed at home. Van Cauter and associates3
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82 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss

also published findings concerning the age-related changes
in slow wave and REM sleep in healthy men.
Sleep Latency and REM Latency
In the meta-analysis by Ohayon and coworkers,5 when
studies that included individuals with sleep and mental dis-
orders were excluded, sleep latency increased only minimally
from ages 20 to 80 (~10 min) (Fig. 63). If patients with
mental and medical disorders were included, there was not
a significant increase in sleep latency with age. This is con-
sistent with more reports of early morning awakening than
sleep onset problems in the healthy elderly. In general, a sleep
latency of 30 minutes or more is considered abnormal. In the
same meta-analysis, the REM latency decreased with age.
TST and Sleep Efficiency
TST decreases with age as does the sleep efficiency (TST
100/TRT) (Fig. 64). There tends to be a more rapid decrease
in TST from childhood to adolescence and then a slower
decrease from age 20 to 80 years. Sleep efficiency decreases
with age, especially after age 50.5
WASO and Stage N1 (as a Percentage of TST)
In the meta-analysis by Ohayon and coworkers,5 WASO and
stage N1 (as %TST) increased from age 20 to 60 years
(Fig. 65). In the analysis of Redline and colleagues,6 the
amount of stage N1 increased over the four quartiles for men
but not for women (Fig. 66).
Stage N2 (as a Percentage of TST)
In the meta-analysis of Ohayon and coworkers,5 the amount
of stage N2 increases with age (Fig. 67A). Redline and col-
leagues6 found stage N2 to increase with age in men but not
in women (see Fig. 67B). This is consistent with the findings
of a decrease in stage N3 in men (see later). The amount of
stage N2 was higher in men than in women when all age
groups were considered.

SLEEP LATENCY
50 Stage N3 (as a Percentage of TST)
45
In the large meta-analysis by Ohayon and coworkers,5 the
40 amount of stage N3 decreased with age (Fig. 68A). The
35
30
25
TOTAL SLEEP TIME
650
Total sleep time (minutes)

20 600
15 550
10 500
5 450
0 400
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Age 350
300
REM LATENCY 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
190 Age
170
SLEEP EFFICIENCY
100
150
95
(% total recording time)

130 90
Sleep efficiency

110 85
80
90
75
70 70
65
50
60
30 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Age
Age
FIGURE 64 Changes in total sleep time and sleep efficiency with age. Both total
FIGURE 63 The sleep latency increases and rapid eye movement (REM) latency sleep time and sleep efficiency decrease in older individuals. From Ohayon MM,
decreases with age. From Ohayon MM, Carskadon MA, Guilleminault C, Viteiello MV: Meta- Carskadon MA, Guilleminault C, Viteiello MV: Meta-analysis of quantitative sleep
analysis of quantitative sleep parameters from childhood to old age in healthy individuals: parameters from childhood to old age in healthy individuals: developing normative sleep
developing normative sleep values across the human lifespan. Sleep 2004;27:12551273. values across the human lifespan. Sleep 2004;27:12551273.
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 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss 83

WASO STAGE N2
160 75
140 70
120 65

Stage N2 (%TST)
100
60
80
55
60
50
40
45
20
40
0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 35
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Age
A Age
STAGE N1
20.0 STAGE N2
18.0 70
16.0
14.0 Men
65

Stage N1 (%TST)
12.0
10.0
8.0
60
6.0
4.0
2.0 55
0.0
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 Women
Age 50
1 2 3 4
FIGURE 65 Wake after sleep onset (WASO) and stage N1 increase with age. From B Age quartiles
Ohayon MM, Carskadon MA, Guilleminault C, Viteiello MV: Meta-analysis of quantitative
sleep parameters from childhood to old age in healthy individuals: developing normative FIGURE 67 A, The relationship between the amount of stage N2 and age in the study
sleep values across the human lifespan. Sleep 2004;27:12551273. of Ohayon and coworkers.5 Stage N2 increased with age. B, Stage N2 increased with age
only in men in the study of Redline and colleagues.6 The age range for each quartile is
defined in Table 64.

STAGE N1
9 Stage R (as a Percentage of TST)
8 Ohayon and coworkers5 found a decrease in stage R between
Men
20 and 60 years of age (Fig. 69A). Most of the decrease in
Stage N1 (%TST)

7 REM as a percentage of TST was noted between 10 and 35

6 64), there was a small but statistically significant decrease
5
4 Women
3 sleep architecture in normal men. They found an increase in
1 2 3 4
Age quartiles
FIGURE 66 Stage N1 increased with age in men but not women. The age range of
each quartile is defined in Table 64. TST = total sleep time. Data from Redline S,
Kirchner L, Quan SF, et al: The effects of age, sex, ethnicity, and sleep-disordered breathing
on sleep architecture. Arch Intern Med 2004;164:406418.
effect size was greater in men than in women. In the study
by Redline and colleagues,6 the amount of stage N3 (%TST)
decreased with age only in men (see Fig. 68B). The decrease
in stage N3 was associated with increases in stages N1 and
N2. Note that for the entire group of women (all ages), the
amount of stage N3 was higher.
years of age. In the data of Redline and colleagues6 (see Table
in stage R with age for both men and women (see Fig. 69B).
Sleep Architecture (as a Percentage of SPT)
Van Cauter and associates3 also published information of
stage W but minimal change in combined stage N1 and N2
(Fig. 610). Their data were expressed as a percentage of
sleep period time. They also found a decrease in stage N3
with age and a decrease in stage R most prominent after age
50 (Fig. 611).
ALTERNATIONS IN REM LATENCY
Various sleep disorders and medications7 are associated with
changes in the REM latency (Table 65). A short nocturnal
REM latency can be seen in patients with narcolepsy, sleep
apnea, and depression. Withdrawal from a REM-suppressing
medication can also shorten the REM latency. A REM latency
of 0 to 15 minutes is often referred to as sleep-onset REM.
Sleep-onset REM is a defining characteristic of narcolepsy.
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84 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss

STAGE N3 STAGE R
70 30
28
60
26
Stage N3 (%TST)

Stage R (%TST)
50 24
40 22
20
30 18
20 16
14
10
12
0 10
5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
A Age A Age

20 Women 24

22
Women
15
Stage N3 (%TST)

20

Stage R (%TST)
18
10 Men
16

Men 14
5
12

0 10
1 2 3 4 1 2 3 4
B Age quartiles B Age quartiles

FIGURE 68 A, Stage N3 (%TST [total sleep time]) for men and women combined
decreases in adults. B, Stage N3 (%TST) decreases with age only in men. The absolute
amount of stage N3 for the study group as a whole was greater in women than in men.
The age range for each quartile is defined in Table 64. A, From Ohayon MM, Carskadon
MA, Guilleminault C, Viteiello MV: Meta-analysis of quantitative sleep parameters from
childhood to old age in healthy individuals: developing normative sleep values across the
human lifespan. Sleep 2004;27:12551273. B, Data from Redline S, Kirchner L, Quan SF,
et al: The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture.
Arch Intern Med 2004;164:406418.
FIGURE 69 Stage R. A, The amount of stage R (%TST [total sleep time]) decreases
with age. Most of the decrease comes between 20 and 30 years. B, There was a small
decrease in rapid eye movement (REM) with age quartile. The age range for each
quartile is defined in Table 64. In this study, only patients older than 37 years were
included. A, From Ohayon MM, Carskadon MA, Guilleminault C, Viteiello MV: Meta-
analysis of quantitative sleep parameters from childhood to old age in healthy individuals:
developing normative sleep values across the human lifespan. Sleep 2004;27:12551273.
B, Data from Redline S, Kirchner L, Quan SF, et al: The effects of age, sex, ethnicity, and
sleep-disordered breathing on sleep architecture. Arch Intern Med 2004;164:406418.

TABLE 65 latency. Medications known to prolong the REM latency

Short and Long REM Latency include tricyclic antidepressants, selective serotonin reup-
take inhibitors, monoamine oxidase inhibitors, and lithium.
SHORT REM LATENCY LONG REM LATENCY
Some substances such as alcohol can also increase the REM
Narcolepsy Ethanol latency.
Depression SSRIs
Withdrawal of REM- Tricyclic antidepressants Gender Differences
suppressing medication Lithium
In adulthood, women of all ages tend to have more stage N3
Sleep apnea Sleep apnea than men at the expense of stages N1 and N2 (stage N1 and
Previous REM deprivation First-night effect N2 are greater in men as %TST) (see Figs. 66 to 68). The
REM = rapid eye movement; SSRIs = selective serotonin reuptake inhibitors. amounts of stage R are similar in men and women.

In depression, REM latencies on the order of 40 minutes

are typical but can be as short as those seen in patients
with narcolepsy. In depression, the first episode of REM
sleep is often prolonged with a higher REM density than
usual. In contrast, a number of other sleep disorders that
fragment sleep such as sleep apnea can prolong the REM
First-Night Effect
The first-night effect was described by Agnew and cowork-
ers8 and Webb and Campbell9 from analysis of individuals
undergoing multiple sleep studies. The phenomenon con-
sists of lower sleep efficiency, lower amount of REM sleep,
and longer REM latency on the first night in the sleep center.
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 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss 85

STAGE W COMPARISON OF SLEEP STAGING

60
BETWEEN THE AASM SCORING MANUAL
AND RECHTSCHAFFEN AND KALES
% of sleep period

40
Given that most previous work on sleep architecture was
based on the scoring manual of Rechtschaffen and Kales
20 (R&K),10 normative values could be altered by the new AASM
scoring manual. Therefore, studies comparing sleep architec-
ture between R&K and the AASM scoring manual are needed.
0 Moser and colleagues11 found that the sleep latency, REM
16-25 26-35 36-50 51-60 61-70 71-83
latency, TST, and sleep efficiency were not affected (similar in
Age
AASM and R&K). The absolute duration of sleep stage and the
STAGE N1  N2 %TST in stage N1 increased and stage N2 decreased using
60 AASM criteria compared with those of R&K. Stage R also dif-
fered but was age-dependent, being slightly higher using
% of sleep period

AASM criteria in older individuals. The amount of stage N3

40
was higher in AASM as expected with use of frontal deriva-
tions to assess slow wave activity (slow waves have the higher
20 amplitude in frontal compared with central derivations).
Danker-Hopfe and associates12 compared interscorer reliabil-
ity between the AASM and the R&K criteria and found slightly
0 better agreement with the AASM criteria, although the differ-
16-25 26-35 36-50 51-60 61-70 71-83
ence was small. Novelli and coworkers13 compared AASM
Age
(e.g., N1) and R&K (e.g., S1) for sleep scoring in children and
FIGURE 610 Changes in stage W and stage N1 + N2 expressed as a percentage of adolescents. They found N1 > S1, N2 < S2, and R < stage REM.
the sleep period time (time from first sleep until final awakening) in normal men. Stage They found a low concordance between the systems. These
W increased with age. There was minimal change in combined stage N1 + N2. studies are only the first of many to be expected in the future.

NORMAL SLEEP IN INFANTS AND CHILDREN

STAGE N3
25 Sleep Architecture in Infants
20 As noted in Chapter 5, sleep stage scoring differs considerably
% of sleep period

between infants and adults. The sleep architecture in infants

15 is also very different from that in adults (Table 66). Infants
10 normally enter sleep via stage R (active sleep for age < 2 mo)
and spend approximately 50% of the TST in this sleep stage.
5 Infants have shorter sleep cycles of approximately 45 to 60
minutes (in contrast to adult cycles of 90100 min).14,15 By 3
0
16-25 26-35 36-50 51-60 61-70 71-83 months of age, the amount of REM sleep starts to decrease.
Age Sleep begins to consolidate into longer nocturnal sleep
periods with shorter naps during the day. Napping is rare
STAGE R
after age 4 years.16
60

Children
% of sleep period

40
The percentage of REM sleep decreases to approximately
30% at age 1 to 2 years and 20% to 25% at 3 to 5 years of age.
20 As children move toward adolescence (Table 67), there
tends to be a decrease in stage N3 sleep and stage R with an
increase in stage N2. TST decreases from early childhood to
0 adolescence from 14 hours at age 1 down to 9 hours in early
16-25 26-35 36-50 51-60 61-70 71-83
adolescence.16 Typical values for sleep parameters are listed
Age
in Tables 68 and 69.1719
FIGURE 611 Change in stage N3 and stage R (as a percentage of sleep period time)
with age in a group of normal men. Stage N3 decreased in the older age range as did AROUSALS
stage R after age 50. From Van Cauter E, Leprousl R, Plat L: Age-related changes in slow
wave sleep and REM sleep and relationship with growth hormone and cortisol levels in Chapter 3 presents the scoring criteria for arousals.2,20
Scoring of arousals is important because frequent arousals
healthy men. JAMA 2000;284:861868.
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86 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss

TABLE 66 TABLE 68
Normal Sleep Infants and Children Typical Sleep Architecture Values for Normal
INFANTS < 3 mo
Children Aged 118

Stage R (REM sleep, active sleep) at sleep onset. PARAMETER USUAL VALUES

Total sleep time 1618 hr. Sleep efficiency (%) 89%, large variability

Sleep episodes of 34 hr duration interrupted by feeding. Sleep latency (min) 23 min, large variability

Sleep cycles 45- to 60-min periodicity (90100 min in REM latency (min) 87155 (<10 yr)
adults). 136156 (>10 yr)

Stage R about 50% of sleep. Arousal index 916

INFANTS > 3 mo Stage N1 (%TST) 45

Percentage of REM sleep starts to decrease. Stage N2 (%TST) 4456

Entering sleep through NREM sleep instead of stage R. Stage N3 (%TST) 2932 (<10 yr)
2032 (>10 yr)
Sleep consolidates into major episodes with daytime
naps. Stage R (%TST) 1721 (can be higher in
younger children)
CHILDREN
REM = rapid eye movement; TST = total sleep time.
Sleep cycle period does not reach adult values until From Beck SE, Marcus CL: Pediatric polysomnography. Sleep Med Clin
2009;4:393406.
adolescence.
NREM = nonrapid eye movement; REM = rapid eye movement.
From Kahn A, Dan B, Grosswasser J, et al: Normal sleep architecture in infants
and children. J Clin Neurophysiol 1996;13:184197.

35
Current
TABLE 67 Mathur, 1995
Changes in Sleep Childhood to Adolescence 30
Boselli et al, 1998

NO CHANGE DECREASE INCREASE 25

Wong et al, 2004
Arousal index

Gosselin et al, 2002

TST (recording % Stage N3 Stage N2
nonschool days) 20

Sleep efficiency % REM sleep 15

Sleep latency TST (recording
school days) 10
REM = rapid eye movement; TST = total sleep time.
From Kahn A, Dan B, Grosswasser J, et al: Normal sleep architecture in infants 5
and children. J Clin Neurophysiol 1996;13:184197.
5 10 20 30 40 50 60
Age

result in nonrestorative sleep even in the absence of a decre-
ment in TST. The arousal index (ArI, number of arousals/
hour of sleep) in normal individuals increases with age (Fig.
612).2125 Bonnet and Arand21 found the ArI in 51- to
60-year-old individuals and 61- to 70-year-old individuals to
be 21.9 8.9/hr and 21.9 6.8/hr, respectively (mean
standard deviation [SD]). Therefore, the 95% confidence
limits may approach 35/hr in older age groups. Conversely,
an ArI of 25/hr would be high for a young adult. Figure 612
shows the data on the change in ArI with age from several
studies.
SLEEP FRAGMENTATION
Although in clinical practice, sleep fragmentation and
chronic partial sleep deprivation (chronic decreased TST)
commonly occur together, studies have shown that frequent
FIGURE 612 Change in arousal index with age. The data are from references 2126.
Current refers to data from reference 22. From Bonnet M, Arand DL: EEG arousal norms
by age. J Clin Sleep Med 2007;3:271274.
arousals alone can cause decrements in performance and
mood as well as increases in subjective and objective sleepi-
ness. Consolidated episodes of sleep in excess of 10 minutes
are needed for restorative sleep.26,27 When experimental sleep
disturbance occurs more frequently than every 3 minutes
(<3-min episodes of consolidated sleep), there is a sharp
decrease in the sleep latency by the multiple sleep latency test
(MSLT)27 (Fig. 613). This would correspond to an ArI
greater than 20/hr. In sleep studies, some patients may have
comparable ArIs but differ in the amount of preserved con-
solidated sleep. Table 610 lists the common clinical symp-
toms of sleep deprivation. Similar findings can occur with
severe sleep fragmentation.
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 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss 87

Proportion of baseline sleep latency 1.1 TABLE 610

1.0 Clinical Symptoms of Sleep Deprivation
0.9 Longer reaction time

0.8 Lapses in attention

0.7 Lost information

0.6 Poor short-term memory

0.5 Poor mood

0.4 Reduced motivation
0.3 Sleepiness
0 20 10 8 6 5 4 3 Poor performance
Fragmentation index (arousal index) (#/hr) Worse at circadian low points
FIGURE 613 The sleep latency on the multiple sleep latency test (MSLT) decreases Worse when sedentary
sharply when the frequency of sleep fragmentation (arousal index) during a preceding Worse with no feedback
night of sleep is around 20/hr. From Bonnet MH, Arand DL: Clinical effects of sleep Worse with reduced light or sound
fragmentation versus sleep deprivation. Sleep Med Rev 2003;7:297310. Worse with low motivation, interest or novelty
From Bonnet MH, Arand DL: Clinical effects of sleep fragmentation versus
sleep deprivation. Sleep Med Rev 2003;7:297310.
TABLE 69
Total Sleep Duration by Age in Normal Children
AGE SLEEP DURATION (hr SD)
6 mo 14.2 1.9 80
5 nights
70
1 yr 13.9 1.2
sleep latency on MSLT
Percent reduction in

60
2 yr 13.2 1.2
50
3 yr 12.5 1.1 40
7 nights
4 yr 11.8 1.0 30

5 yr 11.4 0.9 20 1 night

10 1 night
6 yr 11.0 0.8
0
7 yr 10.8 0.7 TSD-24 SF-1-24 PSD PSD
5 hrs night 6 hrs night
8 yr 10.4 0.7
TSD-24  24 hours of total sleep deprivation
9 yr 10.1 0.6 SF-1-24  24 hours of sleep fragmentation
10 yr 9.8 0.6 every 1 minute
PSD  partial sleep deprivation
11 yr 9.6 0.6
FIGURE 614 Total sleep deprivation (TSD), frequent sleep fragmentation, and
12 yr 9.3 0.6
chronic sleep restriction all cause significant objective sleepiness. The effects of partial
13 yr 9.0 0.7 sleep deprivation (PSD) accumulate (5 nights have more effect than 1 night). MSLT =
multiple sleep latency test. Data redrawn from Bonnet MH, Arand DL: Clinical effects of
14 yr 8.7 0.7
sleep fragmentation versus sleep deprivation. Sleep Med Rev 2003;7:297310.
15 yr 8.4 0.7
16 yr 8.1 0.7
SD = standard deviation.
From Iglowstein I, Jenni OG, Molinari L, Largo RH: Sleep duration from infancy fragmentation. In partial sleep deprivation, the effects will
to adolescense: reference values and generational trends. Pediatrics increase with repeated nights of partial sleep deprivations.
2003;111:302307.

Selective Sleep Deprivation

Total Sleep Deprivation
Some of the effects of total and partial sleep deprivation are
listed in Table 610 and shown in Figure 614.27 In general,
the sleep latency (nocturnal and MSLT) decreases after both
total and partial sleep deprivation as well as severe sleep
If REM sleep is selectively impaired by induced arousals, the
REM latency decreases and the amount of REM sleep
increases on recovery nights.27 In some patients with obstruc-
tive sleep apnea (OSA) on the first night of continuous posi-
tive airway pressure (CPAP), there may be a large increase
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88 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss

in the amount of stage R (REM rebound). Withdrawal of in stage N3 at the expense of other sleep stages. On the second
REM-suppressant medications can also result in similar night, there may be an increase in REM sleep. Therefore, at
findings. Of note, other patients with OSA have a large least in most patients, stage N3 rebound wins out over stage
increase in stage N3 on first CPAP night. R rebound, at least during initial recovery sleep.

Recovery from Sleep Loss Chronic Partial Sleep Deprivation (Restriction)

The findings during recovery sleep after sleep deprivation are Whereas some members of society suffer from periodic sleep
shown in Table 611.27,28 On the first night, there is an increase restriction for one or two nights, a larger segment likely
suffers from chronic partial sleep deprivation. There is large
TABLE 611
interindividual variability in the tolerance to chronic partial
Recovery from Acute Sleep Deprivation sleep deprivation. Healthy humans appear to require 7 to 8
(Recovery Sleep) hours of sleep. A large-scale dose-response study on chronic
FIRST RECOVERY NIGHT sleep restriction estimated the daily sleep need to average
Shorter sleep latency
8.16 hours per night to avoid detrimental effects on waking
functions. In one study of the psychomotor vigilance test
Less stage W, stage N1, stage N2 (PVT), in which subjects respond to a randomly timed
Longer TST (but 1215 hr; if curtailed, longer TST on two target, the frequency of lapses (missed target due to inatten-
or three recovery nights) tion) increased in proportion to total sleep debt or total
Higher % stage N3
accumulated excess time wake. The sleep deprivation and
partial sleep loss conditions fit the same graph when expressed
Lower % stage R as PVT lapses versus total excess accumulated wake (Fig.
REM latency (unchanged younger, shorter in older adults) 615). This study also found that the subjective feeling of
sleepiness or impairment did not continue to worsen beyond
SECOND RECOVERY NIGHT
a certain point. Therefore, the chronically sleep-deprived
Increase stage R (REM rebound) most prominent in individual does not recognize the degree of impairment.29
younger sleepers The results from this and other studies have demonstrated
TST increased that chronic sleep restriction to less than 7 hours per night
can have significant effects on cognitive functioning.30
Stage N3 normal % TST
Some of the many effects of chronic partial sleep loss are
THIRD RECOVERY NIGHT listed in Table 612. These include decreased performance,
Sleep variables approach normal leptin, and response to immunization with increased corti-
REM = rapid eye movement; TST = total sleep time.
sol, ghrelin (increased ghrelin causes hunger), and insulin
From Bonnet MH: Acute sleep deprivation. In Kryger MH, Roth T, Dement WC resistance.28,3034 Some have hypothesized that the chronic
(eds): Principles and Practice of Sleep Medicine, 5th ed. St. Louis: Elsevier, partial sleep deprivation may contribute to the current
2011, pp 5465.
obesity epidemic.

16 16
14 14
12 12
10 10
PVT lapses

PVT lapses

8 8
6 6
Daily sleep period
4 4
8 hr ( ),
2 2 4 hr ( )
6 hr ( ),
0 0 0 hr ( ) Sleep
deprivation
2 2
0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80
A Cumulative sleep debt (h) B Cumulative excess wakefulness (h)

FIGURE 615 Progressive impairment with greater sleep debt or cumulative excess wakefulness. For example, if a person needs
8 hours of sleep (16 hr of wake tolerated), then after 2 nights of 6 hours of sleep, the cumulative sleep debt is 4 hours or the excess
wake is 4 hours. In A, sleep deprivation causes much greater impairment expressed as sleep debt. B, When expressed as excess
wake, the values are similar to those from chronic sleep loss of equal accumulated wake. PVT = psychomotor vigilance test. From
Van Dongen HPA, Maislin G, Mullington JM, et al: The cumulative cost of additional wakefulness: dose-response effects of
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neurobehavioral function and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117126.
 Chapter 6 Sleep Architecture Parameters, Normal Sleep, and Sleep Loss 89

TABLE 612 Answers

Effects of Chronic Partial Sleep Deprivation
1. B. Stage N1 increases (men only in one study) or stays
INCREASE WITH SD DECREASE WITH SD
the same (women in one study).
Sleepiness Vigilance
(Subjective and objective) Pain tolerance 2. B. Sleep efficiency decreases with age.
Attention lapses Cognition and attention
Norepinephrine Seizure threshold 3. D. Infants enter sleep via active sleep, active sleep com-
Cortisol and ACTH Leptin poses about 50% of TST, infant sleep cycle is about 45 to
Ghrelin (hunger) Acute antibody response 60 minutes.
Insulin resistance to influenza and hepatitis
Medical errors A vaccination 4. B. Lithium increases the REM latency.
Motor vehicle accidents Working memory
Cognitive processing 5. B. Sleep deprivation increases ghrelin but decreases
(addition/subtraction) leptin and the response to immunization. In recovery,
ACTH = adrenocorticotropic hormone; SD = sleep deprivation. sleep increased stage N3 occurs on the initial recovery
Data from references 2933. night. Increased stage R may occur on subsequent
nights.

REFERENCES
1. Kushida CA, Littner MR, Morgenthaler T, et al: Practice
parameters for the indications for polysomnography and
CLINICAL REVIEW QUESTIONS related procedures: an update for 2005. Sleep 2005;28:
499521.
1. Which of the following does NOT decrease with age? 2. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
A. TST. Academy of Sleep Medicine: The AASM Manual for the Scoring
B. Sleep stage N1 (men). of Sleep and Associated Events: Rules, Terminology and Tech-
nical Specifications, 1st ed. Westchester, IL: American Academy
C. Stage N3 (men). of Sleep Medicine, 2007.
D. Stage R. 3. Van Cauter E, Leproult R, Plat L: Age-related changes in slow
wave sleep and REM sleep and relationship with growth
E. REM latency. hormone and cortisol levels in healthy men. JAMA 2000;
284:861868.
2. Which of the following decreases with age? 4. Bliwise DL: Normal aging. In Kryger M, Roth T, Dement W
A. Sleep latency. (eds): Principles and Practice of Sleep Medicine. Philadelphia:
Elsevier, 2005, pp. 2438.
B. Sleep efficiency. 5. Ohayon MM, Carskadon MA, Guilleminault C, Viteiello MV:
C. ArI. Meta-analysis of quantitative sleep parameters from childhood
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values across the human lifespan. Sleep 2004;27:12551273.
3. Which of the following is true about infant sleep? 6. Redline S, Kirchner L, Quan SF, et al: The effects of age, sex,
ethnicity, and sleep-disordered breathing on sleep architecture.
A. Enter sleep via stage R (active sleep). Arch Intern Med 2004;164:406418.
B. Active sleep about 50% of TST. 7. Harding SM, Hawkins JW: Sleep and internal medicine. In
Carney P, Berry RB, Geyer J (eds): Clinical Sleep Medicine.
C. Typical sleep cycle duration is 90 minutes. Philadelphia: Lippincott Williams & Wilkins, 2005, pp.
D. A and B. 456470.
E. A and C. 8. Agnew HW Jr, Webb WB, Williams RL: The first night effect:
an EEG study of sleep. Psychophysiology 1966;2:263266.
9. Webb WB, Campbell S: The first night effect revisited with age
4. Which of the following increase the REM latency? as a variable. Waking Sleeping 1979;3:319324.
A. Depression. 10. Rechtschaffen A, Kales A (eds): A Manual of Standardized
B. Lithium. Terminology Techniques and Scoring System for Sleep Stages
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C. Narcolepsy. Brain Research Institute, UCLA, 1968.
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according to AASM and Rechtschaffen & Kales: effects of sleep
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C. Augmented response to immunization. 13. Novelli L, Ferri R, Bruni O: Sleep classification according to
AASM and Rechtschaffen and Kales: effects on sleep scoring
D. Stage R rebound before stage N3 rebound in recovery parameters of children and adolescents. J Sleep Res 2010;19:
sleep. 238247.
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14. Kahn A, Dan B, Grosswasser J, et al: Normal sleep architecture
in infants and children. J Clin Neurophysiol 1996;13:184197.
15. Seldon S: Polysomnography in infants and children: In Sheldon
SH, Ferber R, Kryger MH (eds): Principles and Practice of
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16. Iglowstein I, Jenni OG, Molinari L, Largo RH: Sleep duration
from infancy to adolescence: reference values and generational
trends. Pediatrics 2003;111:302307.
17. Montgomery-Downs HE, OBrien LM, Gulliver TE, et al: Poly-
somnographic characteristics in normal preschool children.
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18. Mason TB, Teoh L, Calabro K, et al: Rapid eye movement
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162169.
19. Beck SE, Marcus CL: Pediatric polysomnography. Sleep Med
Clin 2009;4:393406.
20. Bonnet MH, Doghramji K, Roehrs T, et al: The scoring of
arousal in sleep; reliability, validity, and alternatives. J Clin
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21. Bonnet M, Arand DL: EEG arousal norms by age. J Clin Sleep
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22. Wong TK, Galster P, Lau TS, et al: Reliability of scoring arousals
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23. Mathur R, Douglas NJ: Frequency of EEG arousals from noc-
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Neurobiology of Sleep
Chapter Points
Serotonergic neurons in the DRN are active during
wake, less active during NREM, and even less active
during REM sleep.
Noradrenergic neurons in the LC are active during
wake, less active during NREM sleep, and inactive
during REM sleep.
Histaminergic neurons in the TMN are active during
wake and episodes of cataplexy.
Cholinergic neurons in REM-on areas are active during
REM sleep.
Cholinergic neurons in wake/REM-on areas are active
during wake and REM sleep.
Neurons in the VLPO are active during sleep and
inactive during wake. They contain GABA and galanin.
Hypocretin neurons in the lateral and posterior
hypothalamus project to many areas of the brain
important for the control of wake and sleep. They
stabilize transitions between wake and sleep.
Hypocretin neurons are absent (or very decreased) in
patients with narcolepsy with cataplexy. These patients
also have low or undetectable cerebrospinal fluid
hypocretin-1.
The hypotonia of REM sleep is due to a combination of
inhibition and dysfacilitation.
The brainstem regions involved in hypotonia include
the subcoeruleus area (sublateral dorsal area), areas
of the medulla and interneurons inhibiting the spinal
cord motor neurons (glycine and GABA).
In 1930, von Economo published findings of an autopsy
study of the brains of patients dying from encephalitis lethar-
gica.1,2 Von Economo found that patients with damage to the
posterior hypothalamus and rostral midbrain often had
excessive sleepiness, whereas those with injury to the ante-
rior hypothalamus had unrelenting insomnia. Based on
these observations, he hypothesized that the anterior hypo-
thalamus contained neurons that promoted sleep, whereas
neurons near the hypothalamus-midbrain junction helped
promote wakefulness. Decades later, the importance of those
areas of the brain for sleep and wake, respectively, has been
increasingly understood. A number of major brain areas
involved in control of wake and sleep, their abbreviations,
Chapter 7
and major associated neurotransmitters (neuromodulators)
are listed in Table 71.36
The term neurotransmitter is currently applied to situa-
tions in which one presynaptic neuron directly influences
another postsynaptic neuron. In neuromodulation, a given
neurotransmitter regulates the activity of diverse popula-
tions of neurons in the central nervous system. Examples of
neurotransmitters that are also neuromodulators include
acetylcholine (ACh), serotonin (5HT), dopamine (DA), and
histamine (HA). Neurons are often characterized with
respect to sleep by when they are most active.3 Some neurons
are active during wake, during rapid eye movement (REM)
only (REM-on), during REM and wake (wake/REM-on),
during nonrapid eye movement (NREM) only (NREM-on),
or during NREM and REM sleep (Fig. 71). Figure 72
shows sections through important brainstem areas involved
in the regulation of wake and sleep and identifies important
brain regions.
MAJOR BRAIN AREAS IMPORTANT FOR
SLEEP AND WAKE
Hypothalamic Areas
Lateral Hypothalamus
Neurons in the lateral and posterior hypothalamus are the
sole source of the awake-promoting neuropeptides hypocre-
tin 1 (Hcrt1) and hypocretin 2 (Hcrt2), also known as Orexin
A and Orexin B, respectively.7,8 Hcrt1 can attach to both
Hcrt1 and 2 receptors, whereas Hcrt2 attaches only to Hcrt2
receptors. Patients with narcolepsy with cataplexy have loss
of 90% or more of Hcrt-producing neurons and have low to
undetectable cerebrospinal fluid (CSF) levels of Hcrt1.9,10
One study of a few patients with narcolepsy without cataplexy
found partial loss of Hcrt neurons.11 Canine narcolepsy is
due to a mutation in the gene for the Hcrt2 receptor.
Hcrt neurons send abundant excitatory projections to the
dorsal raphe (Hrct1 and Hcrt2 receptors) nucleus, the locus
coeruleus (Hcrt1 receptors), and the tuberomammillary
nucleus (Hcrt2 receptors) (Fig. 73). These areas in turn
send inhibitory projections to Hcrt neurons. Hcrt neurons
have a strong excitatory effect on the cholinergic neurons of
the basal forebrain that contribute to cortical arousal but
have no effect on GABAergic sleep-promoting neurons
within the ventrolateral preoptic (VLPO) area.
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91
92 Chapter 7 Neurobiology of Sleep

TABLE 71
Brain Areas important for Sleep
AREA ABBREVIATION NEUROTRANSMITTER
Lateral dorsal tegmentum LDT Acetylcholine (ACh)
Pedunculopontine tegmentum PPT Acetylcholine (ACh)
Locus coeruleus LC Norepinephrine (NE)
Dorsal raphe nucleus DRN Serotonin (5HT)
Tuberomammillary nucleus TMN Histamine (HA)
Ventrolateral preoptic area VLPO Gamma-aminobutyric acid (GABA) Galanin
Lateral posterior hypothalamus LPH Hypocretin 1 and 2 (Orexin A, B)

Waking Slow wave sleep REM sleep

EEG
EOG
LGN
EMG
10 s
Cortical and
thalamic
NREM-on
REM-
waking-on
PGO-on
REM-off
REM-on

FIGURE 71 Activity of different neurons during wake, nonrapid eye movement (NREM), and rapid eye movement (REM) sleep. EEG =
electroencephalogram; EMG = electromyogram; EOG = electro-oculogram; LGN = lateral geniculate nucleus; PGO = ponto-geniculo-occipital.
From Rechtschaffen A, Siegel J: Sleep and dreaming. In Kandel E, Schwartz JH, Jessell TM (eds): Principles of Neural Science, 4th ed. New York:
McGraw-Hill, 2000, p. 940, Fig. 473.

As is discussed later, Hcrt appears to stabilize transitions
between wake and sleep. Hcrt neurons are relatively inactive
in quiet waking but are transiently activated during sensory
stimulation. Mileykovskiy and coworkers12 found that Hcrt
cells are silent in slow wave sleep and tonic periods of
REM sleep, with occasional burst discharge in phasic REM
(Fig. 74). Hcrt cells discharge in active waking and have
moderate and approximately equal levels of activity during
grooming and eating and maximal activity during explor-
atory behavior. The authors of this study concluded that Hcrt
cells are activated during emotional and sensorimotor condi-
tions similar to those that trigger cataplexy in narcoleptic
animals.
Ventrolateral Preoptic Nucleus
The VLPO is an area in the hypothalamus containing neurons
active during sleep. Most sleep-active neurons in the VLPO
are believed to be active during both NREM and REM sleep
(Fig. 75).13 Many of the VLPO neurons are activated by
sleep-inducing factors including adenosine and prostaglan-
din D2. These neurons are sensitive to warmth, and heating
this area of the brain increases their activity and decreases
wake. A compact group of VLPO neurons (VLPO cluster)
projects to the tuberomammillary nucleus (TMN) and
inhibits the neuronal activity of that area. A second group of
VLPO neurons is located dorsal and medial to the VLPO
cluster neurons and the group is called the extended VLPO
(eVLPO) by some authors.14 The eVLPO neurons make up
the majority of the projections to the dorsal raphe nucleus
(DRN) and locus coeruleus (LC) as well as to the interneu-
rons of the lateral dorsal tegmental/pedunculopontine teg-
mental (LDT/PPT) region.14 One study showed a subset of
neurons in the eVLPO were more active during REM than
NREM.14 However, most VLPO neurons appear to be active
during both NREM and REM. The neurons in the VLPO
contain the neurotransmitters/neuromodulators gamma-
aminobutyric acid (GABA) and galanin. The VLPO neuro-
nal projections to the DRN, LC, and TMN are inhibitory
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 Chapter 7 Neurobiology of Sleep 93

A B C

SI
1
VLPO TM

D
a b c d e f
E F

PPT
DR LC
LDT
PnO

FIGURE 72 AF, Major brainstem areas important for sleep in the rat brain at various sections. Center, A lateral view of the brain shows locations of the
sections depicted (af). A, Ventrolateral preoptic area (VLPO). B, Substantia innominata (SI). C, Tuberomammillary nucleus (TM). D, Pedunculopontine
tegmentum (PPT) and dorsal raphe nucleus (DR). E, Lateral dorsal tegmentum (LDT). F, Locus coeruleus (LC) and pontine reticular nucleus, oral part
(PnO). The PnO in the rat is homologous to the medial pontine reticular formation in the cat. AF, From Baghdoyan HA, Lydic R: Neurotransmiters and
neuromodulators regulating sleep. In Bazi CW, Ballow BA, Sammaritan MR (eds): Sleep and Epilepsy: The Clinical Spectrum. Amsterdam: Elsevier Science, 2002,
pp. 1744.

10 **
Cortex **
**
Orexin
**
Firing rate (sp/sec)

**
**
BF 5
PPT *
TMN SN Raphe LDT

VTA LC
g

EM

EM

EM
rin

in

tin

ak
om

R
Ea

tw
o
pl

c
ro

e
Ex

ni

i
as
ui
G

To
Q

Ph

FIGURE 73 Orexin (hypocretin) neurons in the lateral hypothalamic area innervate

all of the ascending arousal systems, as well as the cerebral cortex. BF = basal forebrain;
LC = locus coeruleus; LDT = lateral dorsal tegmental; PPT = pedunculopontine
tegmental; SN = substantia nigra; TMN = tuberomammillary nucleus; VTA = ventral
tegmental area.
FIGURE 74 Orexin (hypocretin) neurons are active during wake and quiet during
nonrapid eye movement (NREM) sleep with some activity only during phasic rapid eye
movement (REM) sleep. *P < .05, **P < .01 Bonferroni t test. From Mileykovskiy BY,
Kiyashchenko LI, Siegel JM: Behavioral correlates of activity in identified hypocretin/Orexin
neurons. Neuron 2005;46:787798.
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94 Chapter 7 Neurobiology of Sleep

Awake NREM sleep REM

30

Spikes/sec
20

10
0

EMG

EEG

100 sec

FIGURE 75 Neurons of the ventrolateral preoptic (VLPO) are active during both nonrapid eye movement (NREM) and rapid eye movement
(REM) sleep. EEG = electroencephalogram; EMG = electromyogram. From Szymusiak R, Gvilla I, McGinty D: Hypothalamic control of sleep. Sleep
Med 2007;8:291301.

NREM Sleep Tuberomammillary Nucleus

Histaminergic neurons are confined to the posterior hypo-
thalamus in the area called the tuberomammillary nucleus.
TMN neurons project to the cerebral cortex, amygdala, sub-
stantia nigra (SN), DRN, LC, and nucleus of the solitary
tract. HA acting at H1 receptors is associated with wakeful-
VLPO ness, and antihistamines (H1 receptor blockers) cause
drowsiness or sleep. Conversely, H3 receptor agonists cause
PPT sleepiness possibly by stimulating autoregulatory receptors
LDT
TMN SN Raphe that decrease HA release. The TMN receives stimulatory
VTA LC input from the lateral hypothalamus (Hcrt). The TMN firing
rate is high during wake, lower during NREM, and absent
during REM.3 In contrast to REM sleep, during attacks of
cataplexy, TMN neurons have a high firing rate associated
with preservation of consciousness.15 Low CSF HA has been
found in patients with narcolepsy with and without low
FIGURE 76 Inhibitory projections from the ventrolateral preoptic area (VLPO; Hcrt.16,17 The low HA may be a marker rather than a cause
gamma-aminobutyric acid, galanine) during nonrapid eye movement (NREM) sleep to
of sleepiness because lesions of the TMN have minimal effect
the tuberomamillary (TMN), the raphe area, locus coeruleus (LC), and pendunculopontine
on wakefulness. However, this may simply mean that HA is
lateral/dorsal tegmentum (PPT/LDT) area, substantia nigra (SN), and ventral tegmental
area (VTA). From Espana RA, Scammell TE: Sleep neurobiology for the clinician. Sleep not essential for wakefulness in general. HA may be impor-
2004;27:811820. tant at the onset of wakefulness.

(Fig. 76). The neurons in the VLPO receive inhibitory
projections from the DRN, LC and TMN. Destruction of
the VLPO impairs sleep. A group of sleep-active neurons
in the median preoptic nucleus (MnPO) was described after
the identification of the VLPO.13 Similar to VLPO cells, a
subset of MnPO neurons expresses c-Fos and discharges
more rapidly during NREM and REM sleep. Interestingly,
unlike VLPO neurons, the MnPO cells also fire faster during
prolonged wakefulness (which increases sleep pressure).
There is no evidence that lesions of the MnPO area impair
sleep.
Brainstem Regions
Dopamine Regions
Neurons producing dopamine (DA) are abundant in the SN
and ventral tegmental area (VTA). Previously, studies sug-
gested that DA neurons do not change their firing rates
substantially across sleep stages.3 However, extracellular
DA levels are high in several brain regions during wakeful-
ness. Whereas the average rate of firing of the VTA neurons
does not change across states, they have burst firing during
wake that releases more DA. Recent work has identified DA
cells in the ventral periaqueductal gray (vPAG) that are wake
active.18 The vPAG contains DA neurons that are active
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 Chapter 7 Neurobiology of Sleep 95

(express Fos) during wakefulness but not sleep. DA neurons REM sleep but not wake or NREM sleep. Wake/REM-on
in the vPAG project to and receive input from cholinergic neurons are active during wake and REM sleep (Table 72
neurons in the LDT area, Orexin neurons, VLPO, and pre- and Fig. 78).19 Other cholinergic neurons in the basal fore-
frontal cortex. Loss of vPAG DA neurons promotes sleep. brain (BF) project to the cortex, hippocampus, and amyg-
DA agonists acting at D1, D2, and D3 receptors increase dala. The firing rate of these neurons is also high during wake
waking and decrease NREM and REM sleep. Exactly which and REM and low during NREM sleep.
DA neurons are important for maintenance of wakefulness
is not clear. DA blockers of D1 and D2 receptors can promote
sleep. In patients with low DA activity such as in Parkinsons
disease, low doses of DA agonists (pramipexole, ropinirole) TABLE 72
that bind D2/D3 autoreceptors on DA neurons can actually Activity of Brain Areas Important for Wake
cause sleepiness by reducing DA signaling. Amphetamines and Sleep
promote wakefulness by increasing DA signaling.
WAKE NREM REM
Reticular Formation EEG Fast, low Slow, high Fast, low
The reticular formation is a loose collection of neurons voltage voltage voltage
extending from the caudal medulla to the core of the mid-
LDT/PPT
brain. Sections above the mid pons produce coma or hyper-
somnolence. Wakefulness depends on the activity of the Wake-on Active Not active Active
ascending reticular activating system (ARAS). This system REM-on
projects to higher brain centers. One pathway ascends dor- REM-on Not active Not active Very active
sally to the thalamus, and the second ascends ventrally
TMN Active Reduced Absent
through the lateral hypothalamus and forebrain (Fig. 77).
DRN Active Less active Low activity
Dorsal RAS
Lateral Dorsal Tegmentum/Pedunculopontine Tegmentum. LC Active Less active Absent
Neurons in the LDT and PPT areas that are located in the VLPO* Not active Active Active
dorsal midbrain and pons make up the majority of the dorsal Hypocretin Maximally Not active Not active
RAS pathway through the pons and are cholinergic. Some of active
the neurons are active during wake and REM sleep (wake/
REM-on), whereas others are active mainly during REM Dopaminergic Activity previously thought not to be
neurons sleep state dependent.
sleep (REM-on).35 Acetylcholine (ACh) release in the thala-
vlPAG neurons active during wake
mus is high during wake and REM sleep. The cholinergic
*Some neurons in extended VLPO more active during REM than NREM sleep.
neurons from the LDT/PPT densely innervate the thalamus DRN = dorsal raphe nucleus; EEG = electroencephalogram; LC = locus
(especially the medial and intralaminar thalamic nuclei), coeruleus; LDT = lateral dorsal tegmentum; NREM = non-rapid eye
lateral hypothalamus, and midbrain. During wake and REM movement; PPT = pedunculopontine tegmentum; REM = rapid eye
movement; TMN = tuberomammilary nucleus; VLPO = ventrolateral preoptic
sleep, these cholinergic neurons depolarize thalamic relay area; vlPAG = ventrolateral periaqueductal gray.
neurons, thereby activating thalamocortical signaling and Adapted from Saper CB, Chou TC, Scammell TE: The sleep switch:
produce fast cortical rhythms. During NREM sleep, these hypothalamic control of sleep and wakefulness. Trends Neurosci
2001;24:726731.
neurons are inactive. REM-on neurons are active during

VENTRAL RAS DORSAL RAS FIGURE 77 Reticular activating system (RAS). The
ventral RAS includes neurons from the locus coeruleus,
dorsal raphe nuclei, tuberomammillary nucleus (TMN),
and lateral hypothalamus (LH). The dorsal RAS includes
Thalamus
projections from the lateral dorsal tegmental (LDT) and
pedunculopontine tegmental (PPT) areas.

LH Dorsal raphe LDT

TMN nucleus
PPT
Locus
coeruleus Pons

Medulla
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96 Chapter 7 Neurobiology of Sleep

8 ORX LC
TMN
REM-on neurons DRN
Mean ( SEM) discharges/sec
More VLPO
More
active active
6 eVLPO ORX 
LC
TMN
4 DRN VLPO
eVLPO

2 NREM Wake
Stimulatory

0 Inhibitory
A AW QW SWS REM REM
FIGURE 79 Nonrapid eye movement (NREM) flip-flop switch. During NREM, the
ventrolateral preoptic area (VLPO) inhibits hypocretin neurons as well as the locus
4
coeruleus (LC), tuberomammilary nucleus (TMN), dorsal raphe nucleus (DRN) areas
Wake/REM-on neurons
promoting sleep. During wake, the hypocretin neurons stimulate the LC, TMN, and DRN
Mean ( SEM) discharges/sec

areas, which are active and inhibit the VLPO neurons. eVLPO = extended ventrolateral
preoptic area; ORX = Orexin (hypocretin).
3

2
Basal Forebrain
Cholinergic neurons in the BF excite cortical pyramidal cells.
GABA BF neurons disinhibit cortical neurons. Lesions that
1 destroy BF ACh and GABA neurons increase delta power.
B AW QW SWS REM REM

FIGURE 78 Firing rate of rapid eye movement (REM)-on neurons and wake/REM-on
neurons in the PPT/LPT area. AW = active wake; QW = quiet wake; REM+ = REM sleep
with eye movements; REM = REM sleep without eye movements; SEM = standard error
of the mean; SWS = slow wave sleep. From Thakkar MM, Strecker RE, McCarley RW:
Behavioral state control through differential serotonergic inhibition in the mesopontine
cholinergic nuclei: a simultaneous unit recording and microdialysis study. J Neurosci
1998;18:54905497.
CONTROL OF NREM SLEEP
During NREM sleep, the VLPO neurons are active and
inhibit the firing of neurons in the TMN, DRN, and LC (see
Table 72 and Fig. 75). The Orexin neurons do not inner-
vate the VLPO but stimulate the TMN, DRN, or LC more or
less depending on the sleep state. Orexin neurons are active
during wake. This mutually inhibitory system functions as a
flip-flop switch transitioning between the two states (Fig.
79; see also Fig. 78).6

Ventral RAS The ventral RAS projects through the lateral

hypothalamus terminating on magnocellular neurons in the
substantia innominata, medial septum, and diagonal band.
These regions contain neurons that project to the cortex.
The ascending projections of this branch are joined by input
from the TMN and lateral hypothalamus. The ventral RAS
is composed of projections from the DRN (5HT) and LC
(norepinephrine [NE]).
Dorsal Raphe Nucleus DRN serotonergic neurons are active
during wake, less active during NREM, and minimally active
during REM sleep.3 The influences of DRN neurons are
mainly stimulatory. They are part of the RAS network (see
Table 72).
Locus Coeruleus Neurons in the LC utilize NE as the neu-
rotransmitter and innervate wide areas of the brain with
chiefly stimulatory effects. LC firing rates are high during
wake, lower during NREM, and absent during REM sleep
(see Table 72).
FEATURES OF REM SLEEP
The major tonic and phasic features of REM sleep35 are listed
in Box 71. The tonic features include electroencephalogram
(EEG) desynchronization (reduction in cortical EEG ampli-
tude), theta rhythm generation by the hippocampus (saw-
tooth wave in the EEG), suppression of muscle tone (atonia),
absent thermoregulation, penile erections in males, and con-
striction of pupils. The phasic features of REM sleep include
ponto-geniculo-occipital (PGO) waves that precede and
occur during REM sleep, irregular respiration and heart rate
(sympathetic bursts), and REMs (see Fig. 71). The PGO
waves start in the pons and transit to the lateral geniculate
nucleus (LGN) of the thalamus and from there to the occipi-
tal area. PGO waves are believed to be an integral part of
REM sleep but are not seen in the cortical EEG. Recording
requires electrodes placed into the appropriate brain areas.
The density of the PGO waves correlates with the amount of
eye movement measured in REM sleep.
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 Chapter 7 Neurobiology of Sleep 97

BOX 71 REM SLEEP

Characteristics of Rapid Eye Movement Sleep
TONIC FEATURES
1. EEG desynchronization (reduction in cortical EEG
amplitude). Thalamus
2. Theta rhythm generated in hippocampus (saw-tooth
waves in EEG).
 PPT REM-on
3. Suppression of muscle tone (atonia).
LDT neurons
4. Absent thermoregulation (no shivering). 
TMN Raphe
5. Penile erections in males. LC
6. Pupils constrict (parasympathetic dominance). 

PHASIC FEATURES
1. PGO waves: Precede and occur during REM sleep. Medial
A. PGO waves arrive in bursts in association with eye medulla
movements. Motor
B. PGO waves originate in pons, travel to LGN of the neurons
thalamus and then to the occipital cortex.
FIGURE 710 The rapid eye movement (REM)-on cells of the lateral dorsal tegmentum
2. Contraction of middle ear muscles.
(LDT) and pedunculopontine tegmentum (PPT) are inhibited during wake and, to a
3. Irregular respiration and heart rate.
lesser extent, NREM sleep by norepinephrine, serotonin, and histamine from the locus
4. REMs. coeruleus (LC), dorsal raphe nucleus (DRN), and tuberomammilary nucleus (TMN),
EEG = electroencephalogram; LGN = lateral geniculate nucleus; respectively. During REM sleep, these areas (LC, DRN, TMN) are silent, disinhibiting the
PGO = ponto-geniculo-occipital waves; REM = rapid eye movements. REM-on neurons. These neurons activate cholinoceptive neurons in the medial medulla
that ultimately inhibit the motor neurons (atonia of REM sleep). Note that neurons in
the medial medulla feedback and inhibit LC that normally increases motor tone. From
Espana RA, Scammell TE: Sleep neurobiology for the clinician. Sleep 2004;27:811820.

Control of REM Sleep

Several models are proposed for the control of REM
sleep.36,2022 In one model, the activity of REM-on neurons
in the LDT and PPT nuclei is high whereas that in the mono-
aminergic centers is low (TMN, DRN, and LC)4,5 (Fig. 710).
Different populations of REM-on cells in the lateral pontine
tegmentum (LPT) and PPT stimulate effector cells in the
medial pontine reticular formation (mPRF) (or pontine
reticular nucleus, oral part [PnO] in the cat). The neurons in
the mPRF are cholinoceptive. Infusion of cholinergic ago-
nists into this area results in many of the manifestations of
REM sleep. Specific areas in the mPRF provide ascending
projections resulting in PGO waves and REMs. An area
called the pontine inhibitory area (PIA) contains nuclei that
are responsible for muscle atonia.4 It is thought that the area
below the LC that is called the subcoeruleus area (or sublat-
eral dorsal [SLD] area by other authors) is the area initiating
atonia.
In Figure 710, neurons from the LDT/PPT provide an
excitatory projection to area in the medial medulla. The
neurons in that area project to the motor neurons of the
spinal cord. The neurotransmitters GABA and glycine hypo-
polarize the motor neurons resulting in the atonia of REM
sleep. At the same time, neurons in the medial medulla
provide inhibitory projections to the LC. This reduces the
normal LC-provided augmentation of muscle activity. Thus,
both inhibition and dysfacilitation are important.3 Other
authors hypothesize slightly different atonia mechanisms as
discussed later.
Stimulation
Inhibition
c
b
REM-on neurons REM-off neurons
produce REM sleep inhibit REM sleep
d
a
Reciprocal interaction schematic
FIGURE 711 Reciprocal interaction model of rapid eye movement (REM) sleep. The
REM-on population has positive feedback (a), so that the activity grows. This activity
excites the REM-off population (d). The REM-off population then inhibits the REM-on
population (b), terminating the REM episodes. The REM-off neurons have negative
feedback (c), and as the REM-off activity diminishes, the REM-on population is released
from inhibition (b) and the activity grows until another REM episode occurs. From
McCarley RW: Neurobiology of REM and NREM sleep. Sleep Med 2007;8:302330.
A model (in simplified form) for transitions to and from
REM sleep presented by McCarley5 is illustrated in Figure
711. There is reciprocal interaction between REM-off
neurons (LC, DRN) and REM-on neurons (LDT, PPT).
The REM-on population has positive feedback (see Fig.
711, line a) so that the activity increases. This activity
excites the REM-off population (see Fig. 711, line d). The
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98 Chapter 7 Neurobiology of Sleep
REM FLIP FLOP
PPT-LDT
DR-LC


 Glutamate
PC
eVLPO  Glutamate
vIPAG
 GABA 
Orx LPT SLD
GABA
REM-on
REM-off
vIPAG ventrolateral SLD sublateral dorsal PC precoeruleus
periaqueductal tegmentum
gray
FIGURE 712 A flip-flop model for rapid eye movement (REM) sleep in which REM-off
and REM-on neurons mutually inhibit each other. The gamma-aminobutyric acid (GABA)
neurons are inhibitory. DR = dorsal raphe; eVLPO = extended ventrolateral preoptic
area; LDT = lateral dorsal tegmentum; LPT = lateral pontine tegmentum; ORX = Orexin
(hypocretin); PPT = pedunculopontine tegmentum. From Fuller PM, Saper CB, Lu J: The
pontine REM switch: past and present. J Physiol 2007;584:735741.
REM-off population then inhibits the REM-on population
(see Fig. 711, line b), terminating the REM episodes. The
REM-off neurons have negative feedback (see Fig.
711, line c), and as the REM-off activity diminishes, the
REM-on population is released from inhibition and the
activity increases until another REM episode occurs. This
model provides an explanation for the cycles of NREM and
REM sleep that occur during sleep. A more complicated
model includes the influence of inhibitory neurons (GABA)
in several brain areas.5
A different model of control of REM sleep by Lu and
Fuller and colleagues2022 concentrates on different nuclei as
the two parts of reciprocally interacting REM-on and
REM-off areas located in the mesopontine tegmentum (Fig.
712). GABAergic neurons in the REM-off and REM-on
areas mutually inhibit each other. In this REM sleep flip-flop
circuit model, the REM-off GABAergic neurons in the ven-
trolateral periaqueductal gray (vlPAG) and LPT and REM-on
GABAergic cells in the SLD tegmental area mutually inhibit
each other. The SLD in rats is equivalent to the subcoeruleus
area or perilocus coeruleus area in cats. The LDT/PPT and
eVLPO provide inhibitory input to the REM-off neurons.
Hypocretin (Orexin) neurons provide stimulatory input to
the REM-off neurons.
In this model, REM-on glutamatergic neurons in the pre-
coeruleus (PC) and medial parabrachial (PB) areas project
to the medial septumBF and activate the hippocampus
(theta rhythm of REM sleep) and neocortex (Fig. 713).
REM-on glutamatergic neurons in the SLD project to
glycinergic/GABAergic interneurons in the spinal cord that,
in turn, project to anterior horn cell motor neurons inducing
muscle atonia. The SLD glutamatergic neurons also project
BF
Glutamate
REM-on
PC
Glutamate
SLD
Medulla 
Interneuron

Glycine, GABA
Motor
neuron
FIGURE 713 Postulated mechanisms for rapid eye movement (REM) EEG
phenomenon and REM atonia in the flip-flop model of REM sleep. Glutaminergic
neurons of the precoerulus (PC) area project to the basal forebrain (BF). Glutaminergic
neurons of the sublateral dorsal nucleus (SLD; mesopontine tegmentum) project to
the medulla and spinal cord mediating hypotonia. GABA = gamma-aminobutyric
acid. Based on Fuller PM, Saper CB, Lu J: The pontine REM switch: past and present. J
Physiol 2007;584:735741.
to a region of the intermediate ventromedial medulla
(IVMM) containing neurons that project to the spinal ventral
horn. However, it is not known whether this projection is
excitatory or inhibitory nor is it known whether these pro-
jections are direct (i.e., spinal motor neuron) or indirect (i.e.,
spinal interneuron). The interneurons hyperpolarize the
motorneurons with GABA and glycine. As noted previously,
the atonia of skeletal muscles during REM sleep results not
only from the inhibition by GABA and glycine at the alpha
motor neurons but also from dysfacilitationloss of 5HT
and NE stimulation on motorneurons from monoaminergic
nuclei.
In this model, cholinergic and monoaminergic systems
may modulate REM sleep by acting on either the REM-off
or the REM-on groups or on both simultaneously (not
shown). However, the cholinergic and monoaminergic
systems are located external to the REM flip-flop switch. Of
note, this flip-flop model does not account for the periodicity
of alternation between NREM and REM sleep.5 In addition,
neuronal activity in the brainstem on transitions from
NREM to REM is a gradual change. The important projec-
tions from cholinergic areas to the thalamus by REM-on cells
are also not addressed.
Effects of Medications
Given the previous models for NREM and REM sleep, one
can see that antihistamines in general cause sleepiness,
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 Chapter 7 Neurobiology of Sleep 99

cholinergic medications tend to increase REM sleep, and A. LDT/PPT.

serotonergic medications tend to impair sleep.3,23 However, B. LC.
there are 14 different 5HT receptors and some receptors are C. DRN.
autoreceptors. Hence, the effect of serotonergic medications
D. TMN.
is complex.
As mentioned, while HA in general promotes wake, 4. What is the neurotransmitter (neuromodulator) of
medications active at H3 autoreceptors may actually VLPO neurons?
augment sleepiness. Thus, actions of medications depend on A. GABA, galanine.
the specific type of receptor predominantly affected. Some
B. 5HT.
medications work by augmenting the effects of naturally
occurring neurotransmitters (neuromodulators). As dis- C. HA.
cussed in Chapter 25, benzodiazepine receptor agonists D. NE.
augment the effect of GABA at GABA-A receptors, thereby
5. Which of the following neurotransmitters/modulators is
promoting sleep.
responsible for the alerting effects of amphetamine?
Adenosine: A Possible Mediator of Sleepiness A. 5HT.
after Prolonged Wakefulness B. DA.
The concentration of adenosine in the forebrain increases C. NE.
during prolonged wakefulness and returns to normal after D. HA.
recovery sleep.4,5,13 It was hypothesized that the accumula-
tion of adenosine might be the mechanism of sleep homeo- 6. Which of the following is NOT true about hypocretin
static drive build-up. However, adenosine knock-out mice neurons?
still exhibit the effects of sleep restriction on slow wave A. Stabilize wake-sleep transitions.
sleep (increased activity). Therefore, adenosine is likely not B. Active during wake.
the only substance mediating the build-up of pressure for C. Located in the lateral hypothalamus.
sleep during prolonged wakefulness. Adenosine receptor
D. Provide inhibitory input to the LC, DRN.
antagonists (caffeine) have potent effects on maintaining
wakefulness. Caffeine blocks adenosine A1 and A2a recep- 7. What is the major transmitter/neuromodulator of
tors.23 Adenosine binds to A1 receptors on the cholinergic neurons in the DRN?
neurons of the BF, decreasing the firing of these neurons. A. 5HT.
This causes a reduction in cortical arousal. Adenosine also
B. DA.
may decrease GABAergic neuronal activity in the same
area. These BF GABA neurons may have inhibitory activity C. NE.
with respect to the neurons that promote sleep. The D. HA.
later sleep-promoting neurons are themselves GABAergic
8. Which of the following brain areas contains neurons
and project to areas of the brain associated with wake and
active during BOTH wake and REM sleep?
inhibit them.
A. LC.
B. LDT/PPT.
CLINICAL REVIEW QUESTIONS C. DRN.
1. Which of the following brain areas is active during D. TMN.
NREM and REM sleep?
9. During REM sleep, neurons in what area are responsible
A. TMN.
for hypotonia?
B. LC.
A. Subcoeruleus/sublateral dorsal tegmentum.
C. DRN.
B. LDT/PPT.
D. VLPO.
C. LC.
2. Which of the following brain areas is active during D. DRN.
REM sleep? E. TMN.
A. LDT/PPT.
10. What neurotransmitter(s) is believed to mediate the
B. LC. inhibition of spinal motorneurons (by interneurons)?
C. DRN. A. GABA/glycine.
D. TMN. B. Glutamate.
3. Neurons in which of the following areas are active C. 5HT.
during cataplexy but not REM sleep? D. NE.
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100 Chapter 7 Neurobiology of Sleep

Answers 9. Nishino S, Ripley B, Overeem S, et al: Hypocretin (Orexin)

1. D.
2. A.
3. D.
4. A.
5. B.
6. D. Stimulatory input to the LC and DRN.
7. A.
8. B.
9. A.
10. A.
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1. Von Economo C: Sleep as a problem of localization. J Nerv
Ment Dis 1930;71:249259.
2. Reid A, McCall S, Henry JM, Taubenberger K: Experimenting
on the past: the enigma of von Economos encephalitis lethar-
gica. J Neuropathol Exp Neurol 2001;60:663670.
3. Espana RA, Scammell TE: Sleep neurobiology for the clinician.
Sleep 2004;27:811820.
4. Siegel JM: The neurobiology of sleep. Semin Neurol 2009;
29:277296.
5. McCarley RW: Neurobiology of REM and NREM sleep. Sleep
Med 2007;8:302330.
6. Saper CB, Chou TC, Scammell TE: The sleep switch: hypotha-
lamic control of sleep and wakefulness. Trends Neurosci
2001;24:726731.
7. De Lecca L, Kilduff TS, Peyron C, et al: The hypocretins: hypo-
thalamic specific peptides with neuroexcitatory activity. Proc
Natl Acad Sci U S A 1998;95:322327.
8. Sakurai T: Orexins and Orexin receptors: a family of hypotha-
lamic neuropeptides and G protein coupled receptors that
regulate feeding behavior. Cell 1998;92:573585.
deficiency in human narcolepsy. Lancet 2003;355:3940.
10. Thannickal T, Moore RY, Nienhuis R, et al: Reduced number
of hypocretin neurons in human narcolepsy. Neuron 2000;27:
469474.
11. Thannickal TC, Nienhuis R, Siegel JM: Localized loss of hypo-
cretin (orexin) cells in narcolepsy without cataplexy. Sleep
2009;32:993998.
12. Mileykovskiy BY, Kiyashchenko LI, Siegel JM: Behavioral
correlates of activity in identified hypocretin/Orexin neurons.
Neuron 2005;46:787798.
13. Szymusiak R, Gvilia I, McGinty D: Hypothalamic control of
sleep. Sleep Med 2007;8:291301.
14. Lu J, Bjorkum AA, Xu M, et al: Selective activation of the
extended ventrolateral preoptic nucleus during rapid eye
movement sleep. J Neurosci 2002;2:45684576.
15. John J, Wu MF, Boehmer LN, Siegel JM: Cataplexy-active
neurons in the hypothalamus: implications for the role of
histamine in sleep and waking behavior. Neuron 2004;42:
619634.
16. Kanbayhashi T, Kodama T, Kondo H, et al: CSF histamine
contents in narcolepsy, idiopathic hypersomnia and obstruc-
tive sleep apnea syndrome. Sleep 2009;32:181187.
17. Nishino S, Sakurai E, Nevisimalov S, et al: Decreased CSF
histamines in narcolepsy with and without low CSF
hypocretin-1 in comparison to healthy controls. Sleep
2009;32:175180.
18. Lu J, Jhou TC, Saper CB: Identification of wake-active dopami-
nergic neurons in the ventral periaqueductal gray matter.
J Neurosci 2006;26:193202.
19. Thakkar MM, Strecker RE, McCarley RW: Behavioral state
control through differential serotonergic inhibition in the
mesopontine cholinergic nuclei: a simultaneous unit recording
and microdialysis study. J Neurosci 1998;18:54905497.
20. Lu J, Sherman D, Devor M, Saper CB: A putative flip-
flop switch for control of REM sleep. Nature 2006;441:
589594.
21. Fuller PM, Saper CB, Lu J: The pontine REM switch: past and
present. J Physiol 2007;584:735741.
22. Vetrivelan R, Fuller PM, Tong QA, Lu J: Medullary circuitry
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23. Boutreal B, Koob GF: What keeps us awake. Sleep 2004;27:
11811194.

DaneshGroup.com

Monitoring Respiration
Technology and Techniques
Chapter Points
The recommended sensor to detect apnea is a
nasal-oral (oronasal) thermal device.
The recommended sensor to detect hypopnea is the
NP signal (with or without square root linearization).
The NP signal is proportional to the flow squared. The
NP signal tends to underestimate low flow and
overestimate high flow. Flattening of the inspiratory
portion of the NP tracing is suggestive of airflow
limitation and high upper airway resistance.
Although the most sensitive method to detect
respiratory effort is esophageal manometry, RIP is the
recommended method used in most clinical studies.
The RIPsum is an estimate of tidal volume (more
accurate when calibrated).
The relationship between the SpO2 and the
corresponding PaO2 depends on many factors
affecting the position of the oxyhemoglobin saturation
curve (including PaCO2, temperature, and abnormal
hemoglobin).
A valid PETCO2 measurement assumes that the tracing
has an alveolar plateau.
SpO2 utilizes the absorption of two wavelengths of
light while co-oximetry utilizes four wavelengths and
can determine the true fraction of oxyhemoglobin
when significant amounts of COHb or MetHb are
present.
The three major components of respiratory monitoring
during sleep include measurement/detection of airflow,
measurement/detection of respiratory effort, and measure-
ment of arterial oxygen saturation (SaO2). Ancillary moni-
toring may include detection of snoring and recording
surrogates of the arterial partial pressure of carbon dioxide
(PaCO2) including end-tidal partial pressure of carbon
dioxide (PETCO2) and transcutaneous partial pressure of
carbon dioxide (TcPCO2). The techniques employed for
respiratory monitoring are discussed in detail in this chapter.
The criteria for defining important respiratory events are
presented in Chapter 9. The AASM Manual for the Scoring
of Sleep and Associated Events (hereafter referred to as
Chapter 8
the AASM scoring manual)1 outlines rules for scoring
respiratory events. These are discussed in detail in Chapter
9. The AASM scoring manual1 recommends specific sensor
types and techniques to be used for recording respiration
during sleep (Table 81). The recommendations are based
on consensus and evidence from an accompanying system-
atic review of the validity and reliability of scoring respira-
tory events during sleep.2 This review serves as an update of
a previous AASM consensus statement concerning the respi-
ratory definitions and the accuracy of monitoring techniques
published in 1999.3
TECHNIQUES TO MEASURE AIRFLOW OR
TIDAL VOLUME
The techniques used to detect (measure) airflow during sleep
studies are listed in Table 82. The pneumotachograph
(PNT) is the most accurate method to measure airflow
during sleep studies (Fig. 81).2,3 This device quantifies
airflow by measurement of the pressure drop across a linear
(constant) resistance (usually a wire screen)3. The relation-
ship between the pressure change, flow rate, and resistance
is given by the following equation:
Pressure change = Flow Resistance Equation 81
The PNT is worn in a mask covering the nose and mouth.
Although the PNT is commonly used to measure airflow
during sleep research, this device is rarely used during clini-
cal sleep studies.
Thermal devices were the first to be used to monitor
airflow during clinical sleep studies.2,3 These devices actually
detect changes in temperature induced by airflow (cooler
inspired air, warmer exhaled air). The changes in device tem-
perature result in changes in voltage output (thermocouples)
or resistance (thermistors). Thermal sensors are generally
adequate to detect an absence of airflow (apnea), but their
signal does not vary in proportion to airflow.4,5 Therefore,
thermal sensors are not an ideal means of detecting a reduc-
tion in airflow (hypopnea). Figure 82 compares thermal
sensor estimates of minute ventilation with those using an
accurate measurement of tidal volume (the head out of the
box plethysmograph).4 A wide scatter of points illustrates the
poor ability of thermal devices to track changes in tidal
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101
102 Chapter 8 Monitoring RespirationTechnology and Techniques

TABLE 81
American Academy of Sleep Medicine Recommended Sensors

Airflow sensor to detect
apnea
Airflow sensor to detect
hypopnea
Sensor to detect respiratory
effort
Arterial oxygen saturation
Alveolar hypoventilation
(PaCO2)
EMG = electromyogram; PaCO2 = arterial partial pressure of carbon dioxide; PCO2 = partial pressure of carbon dioxide.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specifications, 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.
ADULT PEDIATRIC
Recommended: Same as adult except alternative
Nasal-oral thermal (oronasal) sensor sensors for apnea detection also
Alternative sensor (if recommended sensor signal include the end-tidal PCO2 signal and
is unreliable) summed calibrated respiratory
Nasal pressure (with or without square root inductance plethysmography signal
transformation of the signal)
Recommended: Recommended: same
Nasal pressure (with or without square root Alternative sensors: Nasal-oral thermal
transformation of the signal) device
Alternative sensors (if recommended sensor signal
is unreliable)
Nasal-oral thermal device
Respiratory inductance plethysmography
(calibrated or uncalibrated)
Recommended: Same except muscle EMG not
Esophageal pressure mentioned
Respiratory inductance plethysmography
(calibrated or uncalibrated)
Alternative:
Diaphragmatic or intercostal muscle EMG
Recommended: Same
Pulse oximetry
Insufficient evidence to recommend a sensor Acceptable:
The following may be used if validated End-tidal PCO2 monitoring
End-tidal PCO2 monitoring Transcutaneous PCO2 monitoring
Transcutaneous PCO2 monitoring

volume (and flow). Figure 83 compares thermistor and
thermocouple signals in a nose model with a PNT as the gold
standard (accurate measure of flow).5 Note that thermal
signals and PNT flow are equal at 1 L/sec (by design).
However, as airflow decreases, the thermal signals overesti-
mate flow. This figure illustrates that thermal sensors are not
ideal sensors to detect hypopneas (reductions in flow). The
same study demonstrated that the thermal sensor signal
decreases when the nostrils are large or the thermal sensor
is further from the nares. Of note, thermal devices composed
of polyvinylidine fluoride (PVDF) film may offer a better
estimate of flow6 (Fig. 84). Nasal-oral thermal sensors
usually have a portion of the device placed within or just
outside the nostrils with another portion over the mouth
(detection of oral flow) (Fig. 85). A major advantage of
thermal sensors is that they can detect both nasal and oral
airflow without the need for a cumbersome mask covering
the face.
Measurement of nasal pressure (NP) provides an estimate
of nasal airflow that is more accurate than one obtained with
most thermal sensors.712 NP is measured using a nasal
cannula connected to an accurate pressure transducer.
Because the cannula tips are inside the nares and the other
side of the pressure transducer is open to the atmosphere,
the pressure being measured is actually the pressure drop
across the resistance of the nasal inlet associated with nasal
airflow. The resistance of the nasal inlet is not a constant
(nonlinear). The relationship of NP and flow is given by
Equations 82 and 83.7,10
NP = K1 (Flow )2 K1 = constant Equation 82
Flow = K2 NP. K2 = constant Equation 83
Because NP varies with the square of flow, the NP signal
tends to underestimate airflow at low flow rates and overes-
timate flow at high flows (Fig. 86). The NP signal is linear-
ized by taking the square root (Equation 83) and when
calibrated, it very closely approximates the flow from a PNT
at least over a short period of time (see Fig. 86). However,
in clinical practice, the NP signal rather than the square root
of the signal is most often recorded as an estimate of nasal
airflow. Even when linearized, the NP signal may not provide
an absolutely accurate estimate of total airflow over the entire
night. Changes in cannula position, periods of partial oral
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 Chapter 8 Monitoring RespirationTechnology and Techniques 103

TABLE 82 MINUTE VENTILATION - THERMISTOR VS. PLETHYSMOGRAPHY

Monitoring Airflow or Tidal Volume 150
DEVICE PHYSIOLOGY

Thermistors (% of baseline)
PNT Pressure drop across PNT = Flow
Resistance 100
Flow = Pressure difference/Resistance
PNT usually placed in a mask covering the
nose and mouth
Nasal-oral Changes in temperature induced by airflow 50
thermal result in changes in resistance (thermistor)
device or voltage output (thermocouple)
Accurate for the presence or absence of
airflow 0
0 50 100 150
Can detect nasal and oral airflow
Signal not proportional to flow Plethysmograph signal (head out of box)
(% of baseline)
NP Measures pressure difference across the
nares FIGURE 82 Thermistor signals are not a good estimate of changes in minute
NP = K1 (Flow)2 (K1 and K2 are constants) ventilation (do not accurately track changes in flow or tidal volume). The dark line is the
Flow = K2 NP. line of identity. Reproduced from Berg S, Haight JSJ, Yap V, et al: Comparison of direct and
Flattening of the inspiratory flow contour indirect measurement of respiratory airflow: implications for hypopneas. Sleep
detects airflow limitation 1997;20:6064.
Oral breathing not well detected
RIP RIPsum is an estimate of tidal volume
Most accurate if calibrated
1.5
Time derivative of the RIPsum gives an
estimate of flow
NP = nasal pressure; PNT = pneumotachograph; RIP = respiratory inductance
Thermal flow (volts)

plethysmography.
1.0

PNEUMOTACHOGRAPH
Thermistor
Screen with resistance  R 0.5
Thermocouple

Overestimate at low flows

Flow 0
0 0.5 1.0 1.5
P
P1 P2 Pneumotachograph flow (liters/sec)

FIGURE 83 Thermal devices overestimate the actual flow (underestimate the drop
in flow) as flow decreases. The straight line is the line of identity. Reproduced from Farr
Flow R, Montserrat JM, Rotger M, et al: Accuracy of thermistors and thermocouples as flow-
Pressure
transducer measuring devices for detecting hypopneas. Eur Respir J 1998;11:179182.
P  P1  P2 P  Flow  R

FIGURE 81 The pneumotachograph (PNT) measures airflow by determining the

pressure drop across a linear (constant) resistance.
flow, and obstruction of the cannula by nasal secretions
make the linearized NP signal a less accurate measure of
flow over the entire night.11 Thurnheer and coworkers11
compared the NP and linearized NP signals ( NP.) for
detection of respiratory events with the PNT (flowmeter)
(Fig. 87). The number of apneas and hypopneas per hour
of sleep (apnea-hypopnea index [AHI]) was determined
using each of the three signals (PNT, NP, and linearized NP).
A hypopnea was defined as a reduction in signal to 50% or
less of the baseline. The bias (mean difference between AHI
values) and limits of agreement (2 SD [standard deviation]
of the differences) were determined by comparing the AHI
values detected by the NP versus PNT and the linearized NP
versus PNT signals in each patient. The AHI values from
both the NP and the linearized NP signals showed excellent
agreement with the AHI values determined from the PNT
(flowmeter) (Table 83; see also Fig. 87). The AHI values
detected by the NP signal tended to be slightly higher than
the linearized NP signal, but the differences were usually
small. Of note, when a more stringent criteria was used for
NP events (signal reduction to 25% of baseline), the NP
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104 Chapter 8 Monitoring RespirationTechnology and Techniques

MAXIMUM DEFLECTIONS
70 PNEUMOTACHOGRAPH
Line of identity
60
Flow
50
PVDF sensor

40 Regression
line NASAL PRONGS

30
Flow
20

10
LINEARIZED NASAL PRONGS
0
0 10 20 30 40 50 60 70
Pneumotachograph sensor (liters/minute) Flow

FIGURE 84 PVDF thermal sensor signals appear to be fairly accurate estimates of

airflow. PVDF = polyvinylidene fluoride. Reproduced from Berry RB, Koch GL, Trautz S,
Wagner MH: Comparison of respiratory event detection by a polyvinylidene fluoride film 0 10 20 30 40
airflow sensor and a pneumotachograph in sleep apnea patients. Chest 2005;128: Time (sec)
13311338.

FIGURE 86 Simultaneous flow signals during hypopnea from a pneumotachograph,

nasal prongs (nasal pressure), and linearized nasal prongs (square root transformation
of nasal pressure). The nasal prongs signal decreases more than that of the
pneumotachograph during a reduction in airflow. The linearized nasal prongs signal is
very similar to that of the pneumotachograph. Reproduced from Farr R, Rigau J,
Montserrat JM, et al: Relevance of linearizing nasal prongs for assessing hypopneas and
flow limitation during sleep. Am J Respir Crit Care Med 2001;163:494497.

detection of hypopneas during sleep. A hypopnea was

FIGURE 85 Use of both nasal pressure and a nasal-oral thermal sensor is
recommended to monitor airflow during sleep. Note that the thermal device has an
extension over the mouth to detect oral flow.
results were essentially identical to the linearized NP results.
Recall that NP = K (Flow)2 and, therefore, if flow drops from
1 to 0.5, the NP signal drops to 0.25 NP. Using an AHI of 5/
hr by PNT to diagnose obstructive sleep apnea (OSA), all of
the 20 patients in the study would have been correctly clas-
sified by the linearized NP signal but there would have been
two false positives with the AHI determined by NP (50%
drop).
Heitman and colleagues12 also compared the NP and
linearized NP signals with a full-face mask with PTN for
defined as either a 50% drop in the device signal or less than
a 50% drop in the device signal with an associated arousal
or 3% or greater arterial oxygen desaturation. The intermea-
surement agreements (kappa) between NP and PNT and
linearized NP and PNT signals were both excellent and
essentially identical.
In addition to the signal amplitude, the shape (contour)
of both the PNT and the NP signals during inspiration pro-
vides additional useful information7,8,13 (Fig. 88). During
normal unobstructed flow, the inspiratory shape (contour)
of the NP signal is round (see Fig. 88A), whereas during
airflow limitation (a constant or decreased airflow associated
with an increasing driving pressure), the shape of the PNT
and NP signals is flattened (see Fig. 88C). Of note, airflow
limitation is characteristically present during obstructive
reductions in airflow (hypopnea) or snoring. In contrast,
when reductions in airflow are simply due to a fall in inspira-
tory effort, the NP signal amplitude is reduced but the shape
is round. Airflow limitation is usually associated with an
increased pressure drop across the upper airway (more nega-
tive inspiratory pressure below the site of upper airway nar-
rowing; see Fig. 88C).
The most important limitation of the NP technique is that
approximately 10% of patients are mouth breathers and the
NP signal may be misleading. The NP signal may show
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 Chapter 8 Monitoring RespirationTechnology and Techniques 105

20

nasal pressure - flowmeter (h1)

80

AHI nasal pressure (h1)

Limits of
10
agreement

Difference AHI
60
2 SD
Bias
0 0
40 for NP

20 10
NP NP
NP NP
0 20
0 20 40 60 80 0 20 40 60 80
AHI flowmeter (h1) Mean AHI
A flowmeter  PNT B nasal pressure & flowmeter (h1)

FIGURE 87 A, The relationship of AHI (apnea + hypopnea index) values detected by PNT (pneumotachograph; flowmeter), nasal pressure (NP), and
linearized NP (square root of NP). The linearized NP detects slightly fewer and the NP slightly more events than the PNT. B, A Bland-Altman plot
shows the differences in the NP AHI and the flowmeter AHI plotted against the mean of the two values for each subject. The mean difference in AHI
values (bias) and the spread of the differences (limits of agreement = 2 standard deviations [SD]) for the NP AHI values are also shown. A plot of
differences in the linearized NP and PNT AHI values is also shown (bias and limits of agreement not shown). A and B, Reproduced from Thurnheer R,
Xie X, Bloch KE: Accuracy of nasal cannula pressure recordings for assessment of ventilation during sleep. Am J Respir Crit Care Med 2001;146:19141919.

TABLE 83 recommends nasal-oral thermal sensors for detection of

Comparison of Methods for Detection of AHI with apnea and NP sensors (with or without square root transfor-
the Pneumotachograph (Flowmeter) mation of the signal) for detection of hypopnea (see Table
81).1 Simultaneous use of both NP and nasal-oral thermal
BIAS = MEAN
sensors is recommended and has the additional advantage
DIFFERENCE LIMITS OF
of having a backup sensor if the other airflow detection
OF AHI VALUES AGREEMENT
device fails (see Fig. 85).
(AHI DEVICE (2 SD OF AHI
The AASM scoring manual1 notes that if the recom-
AHI PTN) DIFFERENCES)
mended sensor signal is not reliable, the alternative sensor
DEVICE (EVENTS/hr) (EVENTS/hr)
can be used. In adults, the alternative airflow sensor for
NP (50%)* 3.9 0.8 to 8.5 apnea detection is the NP signal. The alternative sensors for
NP (25%)
0.8 9 to 9.6 hypopnea detections are oronasal thermal flow and respira-

tory inductance plethysmography (RIP; discussed later).14,15
Linearized NP (50%) 0.9 9.9 to 8.1 In children, alternative sensors for apnea detection include
RIPsum
2.6 3.3 to 8.6 the exhaled PCO2 waveform, nasal pressure, and the summed
Time derivative 1.0 5.6 to 7.6
respiratory inductance plethysmography (RIPsum) signal.
RIPsum|| The alternative sensor for hypopnea detection is the nasal-
*NP (50%) hypopnea defined as a drop in NP signal to 50% of baseline with
oral thermal flow sensor.
duration 10 sec. RIP13,14 is another method that can be used to detect

NP (25%) hypopnea defined as a drop in NP to 25% of baseline with apnea and hypopnea (Figs. 810 and 811). The signals from
duration 10 sec.

Linearized NP (50%) hypopnea defined as a drop in square root of NP signal
rib cage (RC) and abdominal bands (AB) sensors can be
to 50% of baseline with duration 10 sec. summed in an uncalibrated manner (RIPsum = RC + AB) or

RIPsum hypopnea defined by a 50% drop in RIPsum signal with duration as a calibrated signal (RIPsum = a RC + b AB) as an
10 sec.
||
Time derivative of RIPsum hypopnea defined by a 50% drop in signal with
estimate of tidal volume (not airflow). Here, RC and AB are
duration 10 sec. signals from bands around the rib cage and abdomen and
AHI = apnea-hypopnea index; NP = nasal pressure; PTN = a and b are calibration factors determined during a cali-
pneumotachograph; RIP = respiratory inductance plethysmography; SD =
standard deviation.
bration procedure. If one takes the time derivative of the
Adapted from Thurnheer R, Xie X, Bloch KE: Accuracy of nasal cannula RIPsum signal, the result is an estimate of airflow (RIPflow).
pressure recordings for assessment of ventilation during sleep. Am J Respir The RIPsum during apnea has minimal deflections (approxi-
Crit Care Med 2001;146:19141919.
mately zero tidal volume) and during hypopnea reduced
deflections (reduced tidal volume). In the case of an obstruc-
minimal deflections (apparent apnea) while the nasal-oral tive apnea (see Fig. 810), the RC and AB deflections must
thermal sensor will continue to show airflow (Fig. 89). As nearly exactly cancel each other (paradox). In the case of
a consequence of this phenomenon, events that are actually hypopnea, there is a reduction in the RIPsum signal (low
hypopneas may be misclassified as apnea if the NP signal tidal volume) as well as both the RC and the AB signals. In
is used to detect apneas. The AASM scoring manual the case of obstructive hypopnea, there may also be paradox
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106 Chapter 8 Monitoring RespirationTechnology and Techniques

Glottic pressure Abrupt

Normal contour resolution
Flattened
Intermediate contour
Cannula flow

0 5 10 15 20 25
Time (sec)

No flow limitation
Inspiratory flow

Inspiratory flow

Inspiratory flow
Driving pressure Driving pressure Driving pressure
A B C

FIGURE 88 Changes in nasal pressure (cannula flow) and pressure recorded below the site of upper airway narrowing (glottic refers to supraglottic
pressure) during a reduction in airflow. At A, the flow is rounded, whereas at C, the flattened airflow contour is associated with an increase in pressure
drop across the upper airway and airflow limitation. AC, Reproduced from Hosslet J, Normal RG, Ayapa I, Rapoport DM: Detection of flow limitation
with a nasal cannula/pressure transducer system. Am J Respir Crit Care Med 1988;157:14811467.

Snore
17 sec
Nasal
pressure

Nasal-oral
thermal sensor

Chest

Abdomen

SpO2

95% 97% 91%

FIGURE 89 The nasal pressure signal shows an absence of airflow, whereas the nasal-oral thermal sensor shows continued airflow. This pattern of airflow is due to oral breathing.
Nasal-oral thermal sensors are the recommended device for detecting apnea. SpO2 = pulse oximetry.

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 Chapter 8
Inspiration
RIPsum
RC (rib cage)
AB (abdomen)
Inspiration
RIPsum
RC
AB
with chest and abdomen moving in opposite directions (see
Fig. 811). If a RIPsum signal is not available, one can detect
hypopnea by a reduction in the RC and AB RIP signals. RIP
is discussed further in the respiratory effort section. In the
previously discussed study of Thurnheer and coworkers,11
detection of apnea-hypopnea by the calibrated RIPsum and
the time derivative of the RIPsum were compared with the
PNT (flowmeter) signal (see Table 83). The AHI values
obtained from the RIPsum and time derivative of the RIPsum
signals showed good agreement with AHI values from the
PNT signal.
MEASURING RESPIRATORY EFFORT
Determination of respiratory effort is essential to classify
apneas as obstructive (continued respiratory effort), central
(absent effort), or mixed (central followed by obstructive
portions). The commonly used methods of detecting respira-
tory effort are listed in Table 84. The most sensitive and
accurate method of detecting respiratory effort is by mea-
surement of esophageal pressure13,1315 (Fig. 812). Changes
Monitoring RespirationTechnology and Techniques 107
FIGURE 810 Obstructive apnea: Respiratory inductance plethy-
smography signals from the rib cage (RC) and abdominal bands (AB)
are summed (RIPsum). The RIPsum is an estimate of tidal volume.
Here, tidal volume is essentially zero (apnea) and RC and AB signals
show paradox (moving in opposite directions). Reproduced from
Berry RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley &
Belfus, 2003, p. 89.
FIGURE 811 Obstructive hypopnea: Respiratory inductance plethy-
smography signals from the rib cage (RC) and abdominal bands (AB) are
summed (RIPsum). The RIPsum is an estimate of tidal volume. Here, tidal
volume is reduced (hypopnea) and RC and AB signals show paradox (moving
in opposite directions). Reproduced from Berry RB: Sleep Medicine Pearls, 2nd
ed. Philadelphia: Hanley & Belfus, 2003, p. 84.
in esophageal pressure are estimates of changes in pleural
pressure that occur during respiration (negative intratho-
racic pressure during inspiration). Esophageal pressure
monitoring can detect rather feeble respiratory efforts even
when RC and AB movements are minimal. In addition, the
size of the pressure deflections provides an estimate of the
magnitude of respiratory effort. As discussed in Chapter 9,
detection of respiratory effortrelated arousals (RERAs)
is most accurately performed with esophageal pressure
manometry. Measurement of esophageal pressure can be
performed using air-filled balloons, fluid-filled catheters, or
catheters with pressure transducers on their tips.13 The tech-
nique does require special equipment and expertise and is
routinely performed in only a few sleep centers. In Figure
812, note that RC and AB effort belts (here RIP) fail to
detect the presence of the progressive increase in inspiratory
effort documented by increasing esophageal pressure excur-
sions during an OSA. Some research sleep studies measure
supraglottic pressure instead of esophageal pressure using a
transducer tip placed just below the tongue base. This allows
measurement of the pressure drop across the upper airway.
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108 Chapter 8 Monitoring RespirationTechnology and Techniques

TABLE 84 Because this site is below the area of upper airway closure or
Measurement of Respiratory Effort narrowing in obstructive respiratory events, supraglottic
pressure can also be used to detect respiratory effort.
METHOD SENSORS COMMENTS
Until recently, the most common method for detecting
Esophageal Esophageal Signal proportional to respiratory effort in clinical sleep studies utilized piezoelec-
pressure balloon changes in pleural tric (PE) sensors connected to bands around the RC and AB.
deflections Transducer- pressure Changes in the tension on the PE transducer as the RC and
tipped Sensitive for
AB expand and contract produce a voltage that can be mea-
catheter detection of
Fluid-filled inspiratory effort
sured. The signal from these devices depends on the degree
catheter Relatively invasive of tension on the transducer. The PE belts are adequate for
detection of respiratory effort in most patients but do not
Intercostal/ Bipolar ECG artifact a really quantify the changes in RC or AB volume. Although
diaphragm recording problem
relatively inexpensive compared with RIP effort belts, the PE
EMG activity using surface Obtaining a good
effort belts may provide misleading information (false
electrodes signal may be
difficult in some absence of respiratory effort), especially if not properly posi-
patients tioned and tensioned.
RIP belts provide a more accurate method of detecting
Chest and Piezoelectric Relatively inexpensive
changes in RC and AB motion during respiration than PE
abdominal belts Signals may not
belts.3,14,15 The inductance of coils in bands around the RC
movement accurately reflect
changes in chest and AB changes during respiration as the RC and AB expand
and abdominal and contract. The band inductance varies proportionately to
volume during the cross-sectional area the band encircles. An oscillator is
respiration applied to each circuit and changes in inductance are con-
verted into a voltage output. The RIP bands consist of wires
Chest and RIP belts Inductance varies
abdominal with cross-sectional
attached to a cloth band in a zig-zag pattern. This produces
movement area subtended by a larger change in inductance for a given change in band
the belt circumference.
Can quantify changes Recall that if the RIP signals are calibrated, the RIPsum
in volume when signal = a RC + b AB is an estimate of tidal volume. Here,
RIP signals are the constants a and b are determined during a calibration
calibrated procedure. The accuracy of the RIPsum signal can deterio-
ECG = electrocardiogram; EMG = electromyogram; RIP = respiratory rate if body position changes or the positions of the bands
impedance plethysmography. change during sleep. Stats and associates15 studied patients

Airflow

Chest

1 sec

Abdomen

Esophageal
pressure

40 cm H2O

FIGURE 812 Esophageal pressure deflections increase during an obstructive apnea that might at first glance appear to be central
apnea (absent inspiratory effort). In this patient, the chest and abdomen effort belt signals showed minimal deflections during
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obstructive apnea. The situation was corrected by increasing the gain of the signals while scoring respiratory events.
 Chapter 8
with sleep apnea using both calibrated RIP belts and esopha-
geal pressure monitoring. In only 9% of patients were
obstructive apneas sometimes misclassified as central apneas
by the RIP belts. In these instances, esophageal pressure
deflections were present when there was no detectable
change in the RIP belt signals. Thus, RIP effort belts are not
100% sensitive for detecting respiratory effort. However, if
the bands are properly positioned and tensioned (sized),
they will detect respiratory effort (if present) in most patients.
The vast majority of sleep centers do not perform RIP belt
calibration. It should be noted that the deflections of uncali-
brated RIP bands do not always accurately reflect the mag-
nitude of inspiratory effort or always show paradox (see Figs.
810 and 811) during obstructive apnea and hypopnea.
Chest-abdominal paradoxical motion is discussed in detail
in Chapter 9.
Respiratory effort can also be measured by recording the
respiratory muscle electromyogram (EMG) signal using
bipolar surface electrodes.1618 The common sites include the
intercostal muscles and the diaphragm (Fig. 813). Surface
diaphragm EMG recording utilizes two electrodes about 2
cm apart horizontally in the seventh and eighth intercostal
spaces in the right anterior axillary line. The right side of the
body is used to reduce electrocardiogram (ECG) artifact.
Intercostal EMG recording often uses the right parasternal
area (second and third intercostal spaces in the midaxillary
line). Inspiratory EMG activity is noted in the intercostal
muscles and the diaphragm during nonrapid eye move-
ment (NREM) sleep. During rapid eye movement (REM)
sleep, the intercostal activity is inhibited but diaphragmatic
activity persists, although often diminished in amplitude
during bursts of eye movements.
R intercostal
EMG
NO therm
Nasal
pressure
CHEST
ABDOMEN
SpO2
Inspiratory
EMG activity
Raw signal
FIGURE 813 An obstructive apnea with respiratory effort monitored by both chest and abdominal respiratory inductance plethysmography (RIP) bands and
right intercostal electromyogram (EMG). The right intercostal EMG signal shows bursts coincident with inspiratory effort (and movement of chest and abdomen).
A blow up of one EMG burst is shown at the bottom of the figure in a raw form and with the electrocardiogram (ECG) artifact minimized. SpO2 = pulse oximetry.
Monitoring RespirationTechnology and Techniques 109
The AASM scoring manual1 recommends use of esopha-
geal manometry or calibrated or uncalibrated RIP belts for
detection of respiratory effort during sleep studies in adults
and children (see Table 81). The measurement of respira-
tory muscle EMG is listed as an alternative method of detect-
ing respiratory effort in adults.
MEASURING SaO2
Continuous measurement of the arterial partial pressure of
oxygen (PaO2) during sleep studies is not feasible. Spot
checks of arterial blood gases (ABGs) are only rarely per-
formed during sleep studies and many facilities do not have
the capability to process arterial blood samples. Instead of
PaO2, SaO2 is estimated during sleep studies by continuous
recording of pulse oximetry (SpO2), typically with finger or
ear probes. The relationship of SaO2 and the PaO2 is given
by the oxyhemoglobin (O2Hb) saturation curve (Fig. 814A).
The curve is also called the oxyhemoglobin dissociation
curve in some texts. The relationship between the SaO2 and
the PaO2 is affected by temperature, hydrogen ion concentra-
tion, PCO2, and 2,3-diphosphoglycerate (2,3-DPG) concen-
tration. An abnormal hemoglobin19 (e.g., hemoglobin S in
Fig. 814B) or changes in acid-base status can influence the
relationship of the SaO2 and the PaO2 in the blood. The P50
is the PaO2 at which hemoglobin is 50% saturated. Normally,
the P50 is approximately 26 mm Hg. A higher P50 implies a
shift to the right, lower oxygen affinity, and a higher PaO2
for a given SaO2.
The total hemoglobin concentration (Hbt) is the sum of
concentrations of oxygenated hemoglobin (O2Hb), deoxy-
genated or reduced hemoglobin (RHB), carboxyhemoglobin
ECG artifact removed
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110 Chapter 8 Monitoring RespirationTechnology and Techniques

Left shift of methemoglobin, and Hbt = total hemoglobin

decrease in concentration.
temperature
H SaO2 % = (O2 Hb) 100 /(O2 Hb + RHb)
100
2-3 DPG
Equation 85
90 PCO2 CaO2 = 1.34 Hb SaO2 + 0.003 PaO2 Equation 86
Arterial oxygen saturation (%)

80
70 Right shift
If COHb or MetHb are present in significant amounts,
60 increase in one can define a fractional saturation based on Equation 87.
temperature This shows that the fractional hemoglobin oxygen saturation
50 H
2-3 DPG
of oxygenated hemoglobin (FO2Hb) depends on the concen-
40
PCO2 trations of COHb and MetHb as well as RHb. An accurate
30 oxygen-carrying capacity can be computed using Equation
20 85 with SaO2 replaced by FO2Hb. FO2Hb is sometimes
10 referred to as the fractional saturation. Using equations
0
similar to Equation 87, fractional concentrations can be
0 10 20 30 40 50 60 70 80 90 100 defined for carboxyhemoglobin (FCOHb), methemoglobin
A PaO2 (mmHg) (FMetHb), and reduced hemoglobin (RHb) as the concen-
tration of each entity divided by the total hemoglobin times
100.
Hb A
100
FO2 Hb ( % ) = O2 Hb 100 (O2 Hb + RHb + COHb + MetHb)
90 Hb S
= O2 Hb 100 Hbt
80
Equation 87
Oxygen saturation (%)

70
60
50
40
30
20
10
0 ated hemoglobin as well as COHb and MetHb. Thus, COHb
0 10 20 30 40 50 60 70
B PaO2 (mmHg)
FIGURE 814 A, The oxyhemoglobin saturation curve. Changes in body temperature,
hydrogen ion concentration, partial pressure of carbon dioxide (PCO2) and the
concentration of 2-3-diphosphoglycerate (2-3 DPG) can shift the curve. B, The
oxyhemoglobin saturation curve for normal hemoglobin (HbA) and sickle hemoglobin
(HbS). PaO2 = arterial partial pressure of oxygen.
(COHb) and methhemoglobin (metHb) (Equation 84).
COHb and MetHb do not bind oxygen but shift the oxyhe-
moglobin saturation curve to the left.20,21 In addition, they
affect the fraction of hemoglobin available for binding to
oxygen. The ability of carbon monoxide to bind Hb is about
240 times that of oxygen.
The SaO2 as defined in Equation 85 is often called the
functional saturation. The arterial oxygen content of the
blood (CaO2) is determined largely by the SaO2 (Equation
86). Here CaO2 is in mLO2/mL, Hb is in g/100mL, 1.34 is
the mLO2/g of fully saturated Hb.
Hbt = O2Hb + RHb + COHb + MetHb
where O2Hb = concentration of oxygenated hemoglobin,
RHb = concentration of reduced hemoglobin, COHb = con-
centration of carboxyhemoglobin, MetHb = concentration
One should note that the SaO2 value supplied by some
clinical laboratories is determined by a measured PaO2 and
the use of a table or computer program to provide a value
for the SaO2. Accurate measurement of SaO2 and FO2Hb
depends on the clinical laboratory using a co-oximeter. This
instrument uses absorption of 4 wavelengths of light to
determine the concentrations of oxygenated and deoxygen-
80 90 100
and MetHb can affect the relationship between PaO2 and
SaO2 (position of the oxyhemoglobin saturation curve) and
the relationship between the SaO2 and the FO2Hb.
In the sleep center, the major purpose of SpO2 is not to
determine the oxygen-carrying capacity of the blood
(depends on FO2Hb) but to infer changes in PaO2 due to
respiratory events. The oxyhemoglobin saturation curve
describes the relationship between O2Hb and the free hemo-
globin (O2Hb + RHb, Hb available for oxygen binding). In
this sense, the ability of the SpO2 to allow correct inference
about the PaO2 depends on the accuracy with which SpO2
reflects the SaO2 (rather than the FO2Hb) and the position of
the oxyhemoglobin saturation curve. As discussed later,
COHb and MetHb also affect the performance of the
2-wavelength oximeters commonly used in clinical settings.
PULSE OXIMETRY
Pulse oximeters22 provide an estimate of the SaO2 by deter-
mining the absorption of two wavelengths of light (660 nm
[red] and 940 nm [infrared]) by capillary blood. This deter-
Equation 84
mines the relative amount of the O2Hb and RHb. The absorp-
tion of radiation at 660 nm is much greater with RHb than
with O2Hb, while O2Hb absorbs more radiation at 940 nm
(Fig. 815A). The ability of SpO2 to determine the SaO2 is
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 Chapter 8 Monitoring RespirationTechnology and Techniques 111

Hemoglobin extinction curves elevated by about 1% compared with the FO2Hb. Fortu-
10 660 nm 940 nm nately, the SpO2 is closer to the SaO2 as determined by Equa-
tion 85 than the FO2Hb. For example, a typical set of values
would be: FO2Hb = 87%, FRHb = 9%, FCOHb = 4%, SpO2
Extinction coefficient

1 RHb = 91%, SaO2 = 87/(87 + 9) = 90.6%. As noted previously, the

oxyhemoglobin saturation curve describes the relationship
between the O2Hb and the free hemoglobin (O2Hb + RHb);
O2Hb hence, the PaO2 is determined based on the measured SaO2.
0.1
As noted previously, COHb can shift the oxygen hemoglobin
COHb saturation curve to the left. However, at the levels of COHb
typically encountered in the sleep center, this should not
0.01
600 640 680 720 760 800 840 880 920 960 significantly affect the PaO2 that can be inferred from the
A Wavelength (nm) SpO2. Conversely, the difference between the SpO2 and the
FO2Hb is larger and is approximately equal to the concentra-
tion of COHb.20
100 MetHb occurs when the normal ferrous state (Fe2+) of the
90 iron moiety in Hb is oxidized to the ferric stage (Fe3+).
80 metHb absorbs nearly equal amounts of red and near-
70 infrared light, giving an R = 1.24 As the concentration of
60 MetHb increases, the pulse oximeter reads closer and closer
SpO2 (%)

50 to 85%. Therefore, methemoglobinemia may cause the SpO2

40
30
20
10
0
0.4 1.0 2.0 3.0
R zocaine, sulfonamides) but is rarely a problem in the sleep
AC660 /DC660
R globinemia (this usually is known before the sleep study).
B AC940 /DC940
FIGURE 815 A, Hemoglobin extinction curves for reduced hemoglobin (RHb),
oxyhemoglobin (O2Hb), and carboxyhemoglobin (COHb) at different wavelengths of
light. Note that y axis is a log scale. B, Empirical curve of the ratio of absorption of
radiation at wavelengths of 660 and 940 nm. AC = the pulse added absorption; DC =
the steady state or background absorbance. Note at R = 1, the arterial oxygen saturation
(SpO2) is 85%. A and B, Adapted from Tremper KK, Barker SJ: Pulse oximetry.
Anesthesiology 1989;70:108109.
based on the empirical observation that the ratio (R) of
absorbance at the two wavelengths is related to the SaO2 (see
Fig. 815B). This relationship (calibration curve) is deter-
mined experimentally by determining R at varying SaO2 for
each oximeter. To specifically determine the absorbance of
arterial blood, the AC (pulse added absorbance) at each
wavelength is divided by the DC (background absorbance)
to account for the effect of the absorption of the radiation by
venous blood and tissue. SpO2 is accurate down to about
70%. Whereas values below 70% are often reported, one
must keep in mind that they probably do not correspond
accurately to the actual SaO2.
As previously mentioned, the accuracy of SpO2 can be
impaired by the presence of COHb23 or MetHb,24 which
absorb light at the two wavelengths (660 and 940 nm) used
by pulse oximeters. In the case of COHb, the absorption of
660 nm is similar to O2Hb and causes a falsely elevated
SpO2 estimate of the FO2Hb. It is estimated that for every 1%
of circulating COHb, the pulse oximeter reading is falsely
to give a falsely low estimate of the SaO2 and, hence, the
PaO2. On the other hand methemoglobin shifts the oxyhe-
moglobin saturation curve to the left and the SaO2 is less
than the FO2Hb as oxygen does not bind methemoglobin.
Methemoglobinemia can occur from medications (e.g., ben-
center unless a patient has an inherited form of methemo-
A number of additional factors can impair the accuracy
of SpO2. These include poor perfusion (patient sleeping on
the finger or hand) and nail polish. If the oximetry signal
seems to fluctuate widely or inappropriately low or high
readings are noted, the probe or probe position should be
changed. When in doubt, the technologist can place the probe
on her or his own finger as a test of oximeter accuracy.
In summary, multiple factors can affect the value of PaO2
that can be inferred from a given SpO2 value measured
during a sleep study. If an abnormal relationship between the
SpO2 and the corresponding PaO2 is suspected based on
clinical history (e.g., sickle cell disease or methemoglobin-
emia) or a surprisingly low SpO2 is found, one can draw an
ABG for measurement of PaO2 and co-oximetry for measure-
ment of SaO2, FO2Hb, metHb, and COHb. This assumes that
such a measurement is available and clinically indicated.
SpO2 AND SLEEP MONITORING
In sleep monitoring, an arterial oxygen desaturation is usually
defined as a decrease in the SpO2 of 3% or 4% or more from
baseline. Note that the nadir in SaO2 commonly follows
apnea (hypopnea) termination by approximately 6 to 8
seconds (longer in severe desaturations) (Fig. 816). This
delay is secondary to circulation time and instrumental delay
(the oximeter averages over several cycles before producing
a reading). Figure 816 identifies the apneas and the corre-
sponding nadirs in saturation. Various measures have been
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112 Chapter 8 Monitoring RespirationTechnology and Techniques

FIGURE 816 Apneas are followed by arterial oxygen

desaturations. Longer apneas are associated with more severe
desaturation. SpO2 = pulse oximetry.

35 sec 48 sec 26 sec

Airflow

SpO2

82% 85%
75%

FIGURE 817 A long averaging time impairs the ability of

oximetry to detect arterial oxygen desaturation. SpO2 = pulse Averaging time 3 sec
oximetry. Reproduced from Jasani R, Sanders MH, Strollo PJ: 100
Diagnostic studies for apnea/hypopnea. In Johnson JT, Gluckman JL,
Sanders MH (eds): Management of Obstructive Sleep Apnea. London:
Martin Dunitz, 2002, p. 68. 90
SpO2 (%)

80

70

Averaging time 3 sec Averaging time 21 sec

100

90
SpO2 (%)

80

70
0 60 120 180 240
Time (s)

applied to assess the severity of desaturation, including com-
puting the number of desaturations, the average minimum
SpO2 during desaturations, the time below 80%, 85%, 90%,
as well as the mean SaO2 and the minimum saturation during
NREM and REM sleep. The time with an SpO2 88% is also
commonly determined.
Oximeters may vary considerably in the number of desat-
urations they detect and their ability to discard movement
artifact. As illustrated in Figure 817, using long averaging
times may dramatically decrease the detection of desatura-
tions.25,26 Here, the results of identical oximeters monitoring
the same patient are shown. The averaging time of one of the
oximeters is increased and there are obvious large differences
in the results. The ability of oximeters to detect desaturations
is especially important in light of the definitions of hypopnea
that depend on an associated desaturation.
The AASM scoring manual1 recommends a maximum
averaging time of 3 seconds at a heart rate of 80 bpm. In
patients with a slow heart rate, a slightly longer averaging
time (at least a 3-beat average) may be needed.
MEASUREMENT OF PaCO2 DURING SLEEP
Documentation of hypoventilation during sleep requires
measurement (or estimate) of the PaCO2. The AASM scoring
manual1 defines sleep-related hypoventilation in adults as an
increase in the PaCO2 during sleep 10 mm Hg compared
with an awake supine value. However, continuous ABG
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 Chapter 8
monitoring during polysomnography to determine the
PaCO2 is not practical. An ABG sample sometimes is per-
formed at the start or the end of the study. The sample can
be used to validate a surrogate measure of PaCO2 such as
PETCO2 or TcPCO2. If an ABG sample is taken just at awak-
ening, it may be used to infer hypoventilation. In children,
an arterialized capillary blood gas is often performed rather
than an arterial sample. The AASM scoring manual1 defines
hypoventilation in children based on a PaCO2 greater than
50 mm Hg for 25% of total sleep time.
PETCO2
Capnography27,28 consists of the continuous measurement
of the fraction of CO2 in exhaled gas. This is usually per-
formed using an infrared sensor and, less commonly, a mass
spectrophotometer. The PCO2 is determined by multiplica-
tion of the fraction of CO2 by (Patm47 mm Hg). Here, the
Patm is the atmospheric pressure (760 mm Hg at sea level)
and 47 mm Hg is the partial pressure of H2O in exhaled gas
at body temperature. A schematic tracing of exhaled PCO2
versus time is shown in Figure 818. During initial exhala-
tion, the dead space (PCO2 = 0) reaches the sensor (phase
1), then a mixture of dead space and alveolar gas (phase 2),
and finally, alveolar gas (phase 3). The alveolar plateau occurs
because the PCO2 in the air from the different alveoli differs
slightly. The differences are larger (slope of alveolar plateau
steeper) in patients with lung disease. The PETCO2 is an esti-
mate of the mean alveolar PCO2 (and, therefore, an estimate
of the PaCO2). Of note, there is a gradient between the
PaCO2 and the PETCO2 (PaCO2PETCO2) with the PaCO2
being typically 2 to 5 mm Hg higher than the PETCO2 in
normal individuals. In lung disease, the gradient can be
much larger. In general, the PETCO2 is a valid estimate of
PaCO2 only if an alveolar plateau is present.
CAPNOGRAPHY - Exhaled CO2 Versus Time
End-tidal PCO2
III
II
0 I 0
Expiration Inspiration
Phases of exhaled PCO2
0 Inspiration
I Dead space (no CO2 exhaled)
II Mixture of dead space and alveolar gas
III Alveolar plateau
FIGURE 818 A schematic tracing of exhaled partial pressure of carbon dioxide (PCO2).
The end-tidal PCO2 is an estimate of the arterial PCO2.
Monitoring RespirationTechnology and Techniques 113
The two common methods of capnography are main-
stream and side stream. In the mainstream method, the
sensor is located directly in the path of exhaled gas. In the
side stream method, gas is continually suctioned through a
tube to a more remote sensor (in the instrument at bedside).
In the side stream approach, nasal cannulas are used to
suction exhaled gas from the nares (Fig. 819). When no
CO2 is exhaled (during inspiration or apnea), the nasal
cannula suctions room air (PCO2 = 0). In the side stream
method, there is a delay in exhaled gas reaching the sensor
so the CO2 tracing is delayed compared with the exhaled
airflow (see Fig. 819).
The exhaled CO2 tracing is sometimes used to indicate
apnea (absence of exhaled PCO2). However, this is not rec-
ommended for two reasons. First, gas sampled by the nasal
cannula may not detect mouth breathing, and second, small
expiratory puffs rich in CO2 may still produce deflections in
the exhaled CO2 trace29 (Fig. 820).
Capnography is used much more frequently during pedi-
atric than in adult sleep studies.13,30 Children may have long
periods of obstructive hypovenilation (see Chapter 9) due to
high upper airway resistance (airflow limitation without dis-
crete apneas or hypopneas). Other than a mild decrease in the
SpO2, the significance of these events would be underesti-
mated except for the demonstration of an increase in PETCO2.
TcPCO2 MONITORING
Measurement of TcPCO230,31 depends on the fact that heating
of capillaries in the skin causes increased capillary blood flow
and makes the skin permeable to the diffusion of CO2. The
CO2 in the capillaries diffuses through the skin and is mea-
sured by an electrode at the skin surface. The measured value
is corrected for the fact that heat increases the skin CO2
production as the measured value exceeds the PaCO2 mea-
sured at 37C. Typically, TcCO2 electrodes are calibrated with
a reference gas. A thermostat controls the heating of the
membrane-skin interface. It is usually recommended that
the probe of most TcPCO2 monitoring devices be moved
every 3 to 4 hours to avoid skin irritation/damage.
The response time of newer TcPCO2 units has improved,
but in general, the measured PCO2 may not increase rapidly
enough to correlate with short respiratory events. However,
TcPCO2 can be a good instrument for documenting trends in
the PCO2 during the night. Figure 821 shows trends in the
SpO2 and TcPCO2. Decreases in the SpO2 occur in association
with increases in the TcPCO2 during episodes of REM sleep.
ACCURACY OF PETCO2 AND TcPCO2
The limitations of both methods for estimating the PaCO2
should be considered by the clinician when interpreting the
data. This is especially true if measured values are not con-
sistent with what is occurring clinically with the patient. The
measurement of PETCO2 and TcPCO2 was not found to be
accurate for determining changes in PaCO2 during sleep by
Sanders and coworkers.32 PETCO2 was especially inaccurate
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114 Chapter 8 Monitoring RespirationTechnology and Techniques

Gas suctioned
Nasal Sensor Side stream method
cannula

Inspiration

Airflow
(nasal press)

Exhaled CO2

CO2 tracing is delayed relative to exhaled airflow with the side stream method

FIGURE 819 The CO2 tracing is delayed relative to exhaled airflow in the side stream method.

Exhaled CO2

Inspiration

Pneumotachograph

0
Expiration

Thermal airflow
at nose and mouth

FIGURE 820 The exhaled CO2 tracing shows continued deflections during inspiratory apnea due to small exhaled puffs of air rich
in CO2. Reproduced from Berry RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley & Belfus, 2003, p. 90.

during simultaneous administration of supplemental oxygen
or during positive airway pressure treatment. Of note,
exhaled gas was sampled from a mask rather than using a
nasal cannula. Another investigation found reasonable
agreement between the PETCO2 and the TcPCO2 during
pediatric polysomnography.30 Storre and colleagues31 found
reasonable agreement between PaCO2 and TcPCO2 values
during noninvasive positive airway pressure titration. The
best agreement was between a given PaCO2 value and the
corresponding TcPCO2 value about 2 minutes later.
The AASM scoring manual1 in the respiratory scoring
rules for adults states that there was insufficient evidence to
recommend a specific method for detecting hypoventilation
during sleep. However, it was stated that PETCO2 or TcPCO2
may be acceptable if validated and calibrated. In the pediatric
rules, it states that acceptable methods for assessing alveolar
hypoventilation are either transcutaneous or end-tidal PCO2
monitoring.1
Concerning PETCO2 monitoring, the clinician should
review the exhaled CO2 tracings to determine whether an
alveolar plateau is present. If an alveolar plateau is not
present, the PETCO2 value may not be an accurate estimate
of PaCO2. Other problems for exhaled PCO2 monitoring
include oral breathing and occlusion of the nasal cannula
with secretions. If tidal volumes are very small, a true alveo-
lar sample may never reach the sensor. If only a mixture of
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 Chapter 8 Monitoring RespirationTechnology and Techniques 115

FIGURE 821 Trends in the arterial oxygen saturation (SpO2)

REM REM and transcutaneous partial pressure of carbon dioxide (TcPCO2)
during the night. Note the simultaneous increase in transcutaneous
PCO2 and the decrease in SpO2 during episodes of rapid eye
90 movement (REM) sleep.
SpO2 (%)

80

70

60
TcPCO2 (mm Hg)

40

20

1 hour

FIGURE 822 Snoring noted both in the snore sensor (applied to

the neck near the trachea) and as a vibration (oscillation) in the
nasal pressure signal. Note that the nasal pressure signal also has a
Nasal flattened shape. SpO2 = pulse oximetry.
pressure

Snore

Chest

Abdomen

SpO2 94%

dead space (PCO2 = 0) and alveolar gas is sampled, the
PETCO2 value will likely be much lower than the PaCO2.
Concerning TcPCO2 measurement, the actual tracings
should also be carefully reviewed. If an abrupt change (offset)
in the TcPCO2 tracing is noted, this suggests a measurement
artifact is present. Most TcPCO2 devices require calibration
at the start of monitoring. Poor application of the sensor or
dislodgment of the sensor during sleep can cause a measure-
ment artifact. There is some advantage to the simultaneous
use of both PETCO2 and TcPCO2 if tolerated. If the values
show reasonable agreement during periods of stable breath-
ing, this increases confidence in their validity. Of course, the
goal standard to validate the accuracy of their measurements
is a simultaneous ABG measurement.
SNORING SENSORS
Snoring is a sound produced by vibration of upper airway
structures. Although snoring sensors are widely used, there
is little published evidence to demonstrate the utility of
measurement/detection of snoring during sleep. When
snoring is present, upper airway narrowing of some degree
can be inferred. There is evidence that vibration of different
areas of the upper airway causes different sounds. However,
the utility of this information remains to be determined.
Snore sensors are usually microphones or PE transducers
that are usually applied to the neck near the trachea. Micro-
phones can also be attached to the upper chest area or the
face. Snoring can also be seen in the NP signal as a rapid
oscillation9,13 in the pressure tracing if an appropriate high-
frequency filter setting (100 Hz) is used and the transducer
is sufficiently sensitive. Of note, some NP transducers have
a choice of output of a filtered or an unfiltered signal. The
unfiltered signal must be used to detect snoring. The AASM
scoring manual1 does not provide guidance on use of snoring
sensors and the signal is not part of the scoring criteria for
respiratory events in adults. Snoring is mentioned in scoring
of RERAs in children. Figure 822 illustrates an example of
snoring. Snoring is visualized in both the snore sensor
applied to the neck and the NP signal.
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116 Chapter 8 Monitoring RespirationTechnology and Techniques

70 clinical importance of using this transformation has not

60 been demonstrated.
PCO2 (mmHg)

50
40 3. B. The PETCO2 provides an estimate of the PaCO2 when
30 a plateau is present. There is a gradient between the
20 PETCO2 and the PaCO2. Usually, the PaCO2 is 2 to
10 5 mm Hg above the end-tidal value. The exhaled PCO2 is
0 the mixture of gas from many alveoli. (Rarely, the PETCO2
Time (sec)
is greater than the PaCO2 due to late emptying of alveoli
FIGURE 823 with very high PaCO2 values).

4. D. When the oxyhemoglobin saturation curve is shifted

CLINICAL REVIEW QUESTIONS
1. The sum of the thorax and abdominal band RIP signals
(RIPsum) is an estimate of:
A. Airflow (flow rate).
B. Tidal volume.
2. Which of the following is NOT true about the nasal pres-
sure signal?
A. More accurate estimate of flow than most thermal
sensors.
B. Signal is proportional to the flow rate.
C. Measures the pressure drop across the nasal inlet.
D. Flattening of the inspiratory flow suggests airflow
limitation is present.
E. NP signal tends to underestimate flow at low flow rates
and overestimate flow at high flow rates.
3. Figure 823 is a schematic of a tracing of exhaled PCO2
during a sleep study. The best estimate of the PaCO2 is
which of the following?
A. 60 mm Hg.
B. Slightly greater than 60 mm Hg.
C. Slightly lower than 60 mm Hg.
D. 30 mm Hg.
E. 25 mm Hg.
4. Which of these can cause a greater than expected PaO2
for a given SpO2?
A. Lower PCO2.
B. Lower temperature.
C. Higher pH (lower hydrogen ion concentration).
D. Higher PCO2.
Answers
1. B. The deflection in the RIPsum is an estimate of tidal
volume. A calibrated RIP signal is a more accurate esti-
mate of tidal volume. The time derivative of the RIPsum
signal is an estimate of flow.
2. B. The NP signal is proportional to the square of the flow
rate. For this reason, a square root transformation of the
NP signal is a better estimate of airflow. However, the
to the right, a given SaO2 is associated with a higher PaO2.
The curve is shifted to the right by an increase in PaCO2
(see Fig. 814).
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Academy of Sleep Medicine: The AASM Manual for the Scoring
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nical Specifications, 1st ed. Westchester, IL: American Academy
of Sleep Medicine, 2007.
2. Redline S, Budhiraja R, Kapur V, et al: The scoring of respira-
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4. Berg S, Haight JSJ, Yap V, et al: Comparison of direct and indi-
rect measurement of respiratory airflow: implications for
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5. Farr R, Montserrat JM, Rotger M, et al: Accuracy of thermis-
tors and thermocouples as flow-measuring devices for detect-
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6. Berry RB, Koch GL, Trautz S, Wagner MH: Comparison of
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7. Norman RG, Ahmed M, Walsben JA, Rapoport DM: Detection
of respiratory events during NPSG: nasal cannula/pressure
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10. Farr R, Rigau J, Montserrat JM, et al: Relevance of linearizing
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sure recordings for assessment of ventilation during sleep. Am
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12. Heitman SJ, Atkar RS, Hajduk EA, et al: Validation of nasal
pressure for the identification of apneas/hypopneas during
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13. Berry RB: Esophageal and nasal pressure monitoring during
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14. Tobin MJ, Cohen MA, Sackner MA: Breathing abnormalities
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UK: Cambridge University Press, 2004, pp. 312.
28. DMello J, Butani M: Capnography. Indian J Anaesthesiol
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29. Berry RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley
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30. Kirk VG, Batuyong ED, Bohn SG: Transcutaneous carbon
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Monitoring RespirationEvent
Definitions and Examples
Chapter Points
An oronasal thermal sensor is recommended for apnea
identification. The nasal pressure signal is
recommended for hypopnea identification. An event
with absent nasal pressure excursions but persistent
oronasal sensor excursions >10% of baseline would
not be scored as an apnea.
In adults, an event may be an RERA or a hypopnea
based on which hypopnea definition is being used.
Hypoventilation in adults is defined as an increase in
the PaCO2 of 10 mm Hg or greater from an awake
supine value.
Hypoventilation in children is defined as a PCO2 greater
than 50 mm Hg for 25% or more of the total sleep time
by either PETCO2 monitoring or TcPCO2 monitoring.
Obstructive apneas and hypopnea in children are
defined based on two missed breaths rather than an
absolute time duration.
Respiratory rules for children are used for patients
younger than 18 years. Adult respiratory scoring rules
may be used for children aged 13 years or older.
In children, central apneas have absent inspiratory
effort throughout the entire duration of the event
and one of the following is met:
1. The event lasts 20 seconds or longer.
2. The event lasts 2 breaths (or the duration of 2
breaths as determined by the baseline breathing
pattern) AND is associated with an arousal, an
awakening, or a 3% or greater desaturation.
RESPIRATORY EVENTS IN ADULTS
History of Respiratory Event Definitions
To understand the origins of the current respiratory event
definitions, a historical perspective is helpful. The apnea-
hypopnea index (AHI) is the number of apneas and hypop-
neas per hour of sleep. This metric is often used to make the
diagnosis of sleep apnea and to grade the severity. Defini-
tions of apnea have been relatively standard (typically absent
or nearly absent airflow for 10 sec), but varying definitions
Chapter 9
of hypopnea (reductions in airflow) have resulted in a float-
ing metric.1 Early studies of patients with obstructive sleep
apnea (OSA) focused on obstructive apnea,2 hence, the name
of the syndrome. However, it soon became obvious that
reductions in airflow (hypopnea) also had clinical signifi-
cance. The importance of hypopnea, defined as a reduction
in airflow associated with a 4% or greater desaturation, was
emphasized by Block and coworkers.3 Gould and colleagues4
noted that some patients fit the clinical picture of OSA but
the majority of their respiratory events were hypopneas
rather than apneas. They defined hypopnea as a 50% reduc-
tion in respiratory inductance plethysmography (RIP) belt
deflections lasting greater than 10 seconds and proposed the
term the sleep hypopnea syndrome. Others have used the
term the obstructive sleep apnea hypopnea syndrome. A
landmark paper on the incidence of obstructive sleep apnea
(Wisconsin cohort study) defined hypopnea as a discernible
reduction in the amplitude of calibrated RIP plus an arterial
oxygen desaturation of 4% or more.5 The Sleep Heart Health
Study,6 a large multicenter population-based investigation,
defined hypopneas as a decrease in airflow or thoracoab-
dominal excursion of at least 30% of baseline for 10 seconds
or more accompanied by a 4% or more decrease in oxygen
saturation.5 Airflow was monitored with an oronasal thermal
sensor and respiratory effort with RIP belts. Using this defi-
nition of hypopnea, the study found associations between an
increase in the AHI and cardiovascular morbidity.
The widespread use of nasal pressure (NP) monitoring
allowed recognition of more subtle and more frequent
changes in airflow during sleep than was possible with
thermal devices.7 It was also recognized that reductions in
airflow from obstructive events not associated with desatura-
tions could be associated with consequences such as arousal
from sleep and sleep fragmentation (upper airway resistance
syndrome).8 Therefore, definitions of hypopnea based on
flow and arousal were proposed. In order to standardize
definitions of respiratory events, a consensus statement was
published in 1992 (Chicago criteria).9 Criteria for an
obstructive apnea/hypopnea event (OAHE) was presented
with no differentiation between obstructive apnea and
hypopnea because both events have similar pathophysiol-
ogy. An OAHE was defined as a 50% or greater reduction
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120 Chapter 9 Monitoring RespirationEvent Definitions and Examples

in airflow from baseline lasting 10 seconds or longer using a TABLE 91

valid measure of breathing OR any discernible reduction in Effects of Varying Hypopnea Definitions on
airflow using a valid measure of breathing during sleep when Interscorer Reliability and Apnea-Hypopnea Index
associated with either an arousal or a 3% or greater arterial (Events by Three Scorers)*
oxygen desaturation. Valid measures of breathing included a
MEAN EVENTS/HR ICC
pneumotachograph, NP, RIPsum (or simultaneous reduc-
tion in both chest and abdominal RIP band signals). A 3% AHI #1 Hypopnea = 30% 25.9 32.9 27.4 0.74
rather than a 4% desaturation was recommended based on reduction in airflow
reanalysis of Wisconsin cohort data showing similar associa- AHI #2 Hypopnea = 30% 11.35 9.97 10.8 0.97
tions with important outcomes using either 3% or 4% desat- reduction in airflow + 3%
urations. A respiratory effortrelated arousal (RERA) was desaturation
defined as an event lasting 10 seconds or longer with a
AHI #3 Hypopnea = 30% 6.08 5.38 5.75 0.99
pattern of progressively more negative esophageal pressure reduction in airflow + 4%
terminated by a sudden change in pressure to a less negative desaturation
pressure and arousal.
The choice of the definition of apnea and hypopnea can AHI #4 Hypopnea = 30% 14.11 14.58 14.06 0.95
reduction in airflow + 3%
make a significant difference in the AHI and, therefore, a
desaturation OR arousal
significant difference in the incidence of OSA.1012 Ideal defi-
nitions of AHI would identify a population with symptoms AHI #5 Hypopnea = 30% 9.75 10.78 10.05 0.94
and with an increased risk of adverse outcomes (if untreated). reduction in airflow + 4%
As previously noted, AHI values based on hypopnea defini- desaturation OR arousal
tions requiring an associated desaturation in large popula- Arousal index 13.5 20.63 17.31 0.54
tion studies have shown that increases in AHI are associated *Hypopnea is defined as a reduction in nasal-oral thermal flow or chest and
with cardiovascular morbidity. Another consideration in abdominal RIP excursions to 70% of baseline for 10 seconds or longer.
AHI = apnea-hypopnea index; ICC = intraclass correlation, a measure of
choosing a definition of hypopnea is the desire to have a high
interscorer reliability; RIP = respiratory inductance plethysmography.
interscorer reliability. Whitney and associates10 reviewed the Adapted from Whitney CW. Gottleib DJ, Redline S, et al: Reliability of scoring
results when three experienced scorers analyzed the sleep respiratory disturbance indices and sleep staging. Sleep 1998;21:749757.
studies of 20 randomly selected patients using different defi-
nitions of hypopnea. The sleep studies had been performed A clinical practice parameter published by the American
using a thermal sensor for airflow. Hypopnea was defined as Academy of Sleep Medicine (AASM) recommended a defini-
a reduction in the nasal-oral thermal flow signal or the chest tion of hypopnea similar to the one used in the population-
and abdominal RIP excursions to 70% of baseline or lower based studies (30% reduction in flow + 4% desaturation).13
for a duration of 10 seconds or longer. There was a very large The rationale for the choice was that large population-based
range of resulting AHIs (Table 91). Using a definition of studies had shown an increased risk of cardiovascular con-
hypopnea based entirely on a reduction in flow magnitude, sequences associated with an increased AHI based on this
there was a reasonably high interscorer reliability (see Table hypopnea definition. The Centers for Medicaid and Medi-
91). However, inclusion of a desaturation criteria in the care Services (CMS) subsequently adopted this practice
hypopnea definition did significantly improve the interscorer parameter definition of hypopnea for establishing criteria for
reliability for identifying these events. One rationale for not continuous positive airway pressure (CPAP) reimbursement
including arousal in hypopnea definitions is that scoring of (http://www.cmshhs.gov/mcd/viewdecisionmemoasp?id=
arousals has relatively low interscorer reliability (see Table 204 2008).
91). However, the reliability of scoring hypopneas with a The recently published AASM scoring manual14 provides
definition using a combination of flow and either arousal or definitions of apnea, hypopnea, and RERAs. There are dif-
desaturation resulted in only slightly lower interscorer reli- ferent respiratory scoring rules for adults and children. An
ability than flow plus desaturation alone. Of note, the method accompanying review15 discussed the evidence for the new
used to define a reduction in flow (nasal-oral thermal sensor respiratory rules. In the following sections, the AASM scoring
versus RIP or NP) and the patient population studied may manual definitions for apnea, hypopnea, and RERA events
affect the changes in the AHI produced by varying defini- are presented (Table 92). Although the new criteria are
tions of hypopnea. Tsai and coworkers12 defined AHI-A as a expected to standardize terminology, the hypopnea contro-
discernible reduction in thoracoabdominal deflection (RIP) versy will likely continue. A recent study by Ruehland and
of 10 seconds or longer associated with a 4% or greater arte- colleagues16 found that compared with a diagnosis of OSA
rial oxygen desaturation and AHI-B as a discernible reduc- based on Chicago criteria, using the AASM recommended
tion in thoracoabdominal deflection longer than 10 seconds definition of hypopnea would result in 40% of patients being
plus either a 4% or greater desaturation OR an arousal. They classified as not having OSA. If the AASM alternative hypop-
found AHI-B was, on average, only about 2 events/hr greater nea definition was used, 25% of the patients diagnosed with
than AHI-A. However, depending on the AHI cutoff criteria, OSA by the Chicago criteria would be classified as negative
AHI-B did diagnose more patients as having OSA. for OSA.
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 Chapter 9 Monitoring RespirationEvent Definitions and Examples 121

TABLE 92
Adult Respiratory Event Rules
Apnea Score apnea when all of the following are met:
Oronasal thermal sensor (or alternative) drops by 90% of baseline.
Duration 10 sec.
At least 90% of events duration must meet apnea amplitude reduction criteria.
Classification
1. Obstructive: continued or increased inspiratory effort for duration of apnea.
2. Mixed
Initially absent inspiratory effort in the first portion of the event.
Resumption of inspiratory effort during second portion of event.
3. Central: Absent inspiratory effort for duration of apnea.
(Desaturation NOT needed to score an apnea.)
Hypopnea recommended All criteria must be met:
NP excursions (or alternative sensor) drop by 30% of baseline amplitude.
Duration 10 sec.
At least 90% of duration must meet hypopnea amplitude criteria.
4% arterial oxygen desaturation from pre-event baseline.
Hypopnea alternative All criteria must be met:
NP excursions (or alternative sensor) drop by 50% of baseline amplitude.
Duration 10 sec.
At least 90% of duration must meet hypopnea amplitude criteria.
3% arterial oxygen desaturation from pre-event baseline
OR arousal.
RERA A sequence of breaths lasting at least 10 sec.
Increasing respiratory effort or flattening of the NP waveform.
Followed by an arousal from sleep.
Does not meet criteria for an apnea or hypopnea.
Hypoventilation* Increase in PaCO2 or validated surrogate 10 mm Hg above a supine awake value.
*For adults, hypoventilation is based on the PaCO2. No other sensor was recommended for documentation of hypoventilation. It was stated that PETCO2 or TcPCO2
may be used as surrogate measures of PaCO2 if there is demonstration of reliability and validity.
NP = nasal pressure; PaCO2 = arterial partial pressure of carbon dioxide; PETCO2 = end-tidal carbon dioxide pressure; RERA = respiratory effortrelated arousal;
TcPCO2 = transcutaneous carbon dioxide pressure.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specifications, 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.

The term respiratory disturbance index17 (RDI) is used by
some sleep centers and publications. In many sleep centers,
the terms RDI and AHI mean the same thing. However, the
2005 AASM practice parameters for indications for polysom-
nography (PSG) defined the RDI as equal to the AHI + RERA
index. Here, the RERA index is the number of RERAs/hr of
sleep. The 1992 Consensus statement of the AASM recom-
mended making a diagnosis of OSA based on the number of
apneas/hypopneas obstructive events + RERAs/hr of sleep
and also presented severity criteria based on this metric.9
However, the term RDI was not specifically used. Of note,
the term RDI was not defined in the AASM scoring manual.
It is important to note the definition of RDI when reading
sleep study reports or publications concerning sleep apnea.
Recommended Respiratory Sensors in Adults14
The sensors and methods for respiratory monitoring are dis-
cussed in detail in Chapter 8. The recommended sensor for
apnea detection is a thermal flow sensor at the nose and
mouth (oronasal thermal sensor). If the thermal signal is
inadequate, the NP signal may be used. The recommended
sensor for hypopnea detection is NP with or without a square
root transformation. If the NP signal is inadequate, either the
oronasal thermal signal or the RIP signal (calibrated or
uncalibrated) may be used. Whether the RIP sum signal or
both chest and abdomen RIP signals are to be used was not
specified. The sensors recommended for detecting respira-
tory effort include esophageal manometry or RIP (calibrated
or uncalibrated). An alternative sensor for detection of respi-
ratory effort is diaphragmatic/intercostals EMG. The sensor
for detection of arterial oxygen desaturation is pulse oxim-
etry. It is recommended that oximeters use a maximal aver-
aging time of 3 seconds at a heart rate of 80 bpm or greater.
At lower heart rates, most oximeters choose the averaging
time based on heart rate and average at least 3 pulses. The
recommended sensor for detection of an RERA (see later) is
esophageal manometry. Flattening in the NP signal or RIP
are alternative sensors that may be used.
Definition of Apnea (AASM Scoring Manual)14
Sensor: The recommended sensor for apnea detection is a
thermal flow sensor at the nose and mouth.
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122 Chapter 9 Monitoring RespirationEvent Definitions and Examples
Apnea Scoring Rules in Adults (AASM
Scoring Manual)14
Apnea Rule: Score an apnea when all of the following criteria
are met:
1. There is a drop in the peak thermal sensor excursion by
90% of baseline.
2. The duration of the event lasts at least 10 seconds.
3. At least 90% of the events duration meets the amplitude
reduction criteria for apnea.
Apnea Types
1. Score a respiratory event as an OBSTRUCTIVE apnea if
it meets apnea criteria and is associated with continued
or increased inspiratory effort throughout the entire
period of absent airflow.
2. Score a respiratory event as a CENTRAL apnea if it meets
apnea criteria and is associated with absent inspiratory
effort throughout the entire period of absent airflow.
3. Score a respiratory event as a MIXED apnea if it meets
apnea criteria and is associated with absent inspiratory
effort in the initial part of the event, followed by resump-
tion of inspiratory effort in the second part of the event.
Figure 91 presents examples of obstructive, central, and
mixed apneas using esophageal pressure to detect respiratory
effort. Figure 92 presents examples of the corresponding
events using chest and abdominal RIP belts.
The nasal-oral thermal sensor and not the NP signal is
used to score apnea. Absent NP signal excursions do not
meet criteria for scoring apnea if nasal-oral thermal sensor
excursions are still present and do not meet criteria for
scoring an apnea. In the event shown in Figure 93, NP
excursions are absent for greater than 10 seconds. However,
the event is not scored as an apnea because the thermal
signal is not decreased by 90% of baseline. The combination
of absent NP excursions and persistent nasal-oral thermal
sensor excursion is likely due to oral breathing. Also note
that the apnea criteria do NOT depend on the presence of
either arterial oxygen saturation (SaO2) or arousal. The
AASM scoring manual states that if the oronasal thermal
signal is not functioning, one then uses the NP signal to
score apnea. Although not specifically recommended by the
AASM scoring manual, one could also use the RIPsum
signal.
Hypopnea Scoring Rules in Adults14
In the AASM scoring manual, two hypopnea definitions are
presented (a recommended hypopnea definition and an
alternate hypopnea definition).
Hypopnea (Recommended)
Score a hypopnea if all of the following criteria are met:
1. The NP signal excursions (or those of the alternative
hypopnea sensor) drop by 30% of baseline.
2. The duration of this drop occurs for a period of at least
10 seconds.
3. There is a 4% or greater desaturation from the pre-event
baseline.
4. At least 90% of the events duration must meet the
amplitude reduction of criteria.
This recommended hypopnea definition is essentially the
definition recommended by the 2001 AASM Clinical Prac-
tice Parameter13 and later accepted by CMS. As discussed
previously, evidence for the use of this definition includes
the fact that a similar definition was used in the Wisconsin
Cohort Study and the Sleep Heart Health Study and that an
increased AHI based on this hypopnea definition was associ-
ated with an increased risk of cardiovascular morbidity in
those studies. In addition, as previously mentioned, defini-
tions of hypopnea using changes in SaO2 tend to have high
interscorer reliability. The respiratory event illustrated in
Figure 94 meets the recommended criteria for a hypopnea
because the NP signal excursions are essentially zero for over
10 seconds and the event is associated with an SaO2 of 4%
or greater.
Hypopnea (Alternative)
Score a hypopnea if all of the following criteria are met:
1. The NP signal excursions (or those of the alternative
hypopnea sensor) drop by 50% of baseline.
2. The duration of this drop occurs for a period of at least
10 seconds.
3. There is a 3% desaturation from the pre-event baseline
or the event is associated with an arousal.
4. At least 90% of the events duration must meet the ampli-
tude reduction of criteria for hypopnea.
The alternative definition of hypopnea is similar to the
1999 AASM Task Force Consensus definition of an obstruc-
tive apnea/hypopnea event. The use of 3% rather than 4% is
based on the fact that reanalysis of some of the large studies
using a 3% desaturationbased instead of a 4% desaturation
based hypopnea definition found similar results.9 The defini-
tion recognizes that some reduction in airflow events are not
associated with a drop in the SaO2 of 4% or greater but are
associated with arousal. Frequent respiratory arousals in the
absence of significant desaturation can result in fragmented
sleep and daytime sleepiness. However, interscorer reliability
of scoring hypopneas with a definition based on either desat-
uration or arousals is slightly lower than with the scoring of
events associated only with desaturations (see Table 91).
Event Duration Rules14
A. Event duration (apnea or hypopnea) is measured from
the nadir preceding the first breath that is clearly reduced
to the beginning of the first breath that approximates
the baseline breathing amplitude (Fig. 95).
B. When the baseline amplitude cannot be easily deter-
mined (underlying breathing variability is large), events
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 Chapter 9 Monitoring RespirationEvent Definitions and Examples 123

Obstructive apnea

Airflow

Esoph
pressure

Central apnea

Mixed apnea

FIGURE 91 Examples of obstructive, central, and mixed apnea. Airflow was recorded using a pneumotachograph in a mask over the nose and mouth and
respiratory effort by esophageal pressure monitoring. The frequent small deflections in the esophageal pressure are cardiac artifact.

can also be terminated when either there is a sustained aasmnet.org/Resources/PDF/FAQsScoringManual.pdf). In

increase in breathing amplitude or, in the case in which
a desaturation has occurred, there is event-associated
resaturation of at least 2%.
Clarification of Event Duration Criteria for Apneas
and Hypopneas
The AASM scoring manual steering committee publishes
responses to questions about the scoring rules and clarifica-
tions as frequently asked questions (FAQs) (http://www.
response to a question concerning event duration, the FAQ
R11 stated that the amplitude criteria to define events need
last for only 9 contiguous seconds. For example, if 9 contigu-
ous seconds of an event has a 90% or greater drop in nasal-
oral thermal sensor excursions, the event is scored as an
apnea even if, based on the event duration rules, the event
lasts for longer than 10 seconds. Of note, an apnea or a
hypopnea is NOT scored unless the event duration is 10
seconds or longer.
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124 Chapter 9 Monitoring RespirationEvent Definitions and Examples

Nasal
pressure
26 sec
NO airflow

Chest
OA

Abdomen

SpO2
98%
91%

Nasal
pressure
28 sec
NO airflow

Chest CA

Abdomen

SpO2
98%
91%

Nasal
pressure
28 sec
NO airflow

Chest MA

Abdomen

SpO2
98%
91%

FIGURE 92 Obstructive apnea (OA), central apnea (CA), and mixed apnea (MA) events are illustrated. NO airflow = the nasal-oral thermal
airflow sensor signal; chest and abdomen = RIP belt signals; SpO2 = pulse oximetry.

RERA Rule in Adults (AASM Scoring Manual)14

Score an RERA, if there is a sequence of breaths lasting at
least 10 seconds characterized by increasing respiratory
effort or flattening of the NP waveform leading to an arousal
from sleep when the sequence of breaths does not meet
criteria for an apnea or a hypopnea (Fig. 96).
RERA Detection
As noted previously, the preferred sensor for the detection
of RERAs is esophageal manometry, although NP and RIP
can be used.14 As discussed in Chapter 8, flattening of the NP
signal is associated with airflow limitation and usually
increasingly negative esophageal pressure (or supraglottic
pressure). Arousal often follows a crescendo increase in
esophageal pressure deflections (at least during nonrapid
eye movement [NREM] sleep) as seen in Figure 97.
However, respiratory arousal can also occur after a long
period of airflow limitation and relatively constant but
increased esophageal pressure deflections. Whereas both
hypoxia and hypercapnia may drive inspiratory effort during
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 Chapter 9 Monitoring RespirationEvent Definitions and Examples 125

Snore
17 sec
Nasal pressure

Nasal-oral
thermal sensor

Chest

Abdomen

SpO2

95% 97% 91%

FIGURE 93 This event is not scored as an apnea because excursions in the nasal-oral thermal sensor do not meet criteria for apnea. The lack of deflections in
the nasal pressure signal is likely due to oral breathing during the event. The event would meet criteria for hypopnea using either the recommended or the alternate
American Academy of Sleep Medicine (AASM) criteria. SpO2 = pulse oximetry.

44 sec

Nasal pressure

Nasal-oral
thermal flow

Chest

Abdomen
A
B
SpO2
98% 92%

FIGURE 94 An event meeting the recommended definition of hypopnea. The amplitude of the nasal pressure signal drops by more than 30% of baseline for
well over 9 contiguous seconds and the event duration is longer than 10 seconds. In addition, the event is associated with a greater than 4% desaturation. Note
the paradox in the chest and abdomen tracings at A during the event but not at B after the event. SpO2 = pulse oximetry. The vertical lines are 30 seconds apart.

obstructive respiratory events, it is the magnitude of the
inspiratory effort (magnitude of esophageal pressure excur-
sion) and the threshold for arousal that determine whether
arousal occurs.18 During experimental mask occlusion in
normal subjects, arousal usually occurs when esophageal
pressure deflections (negative pressure) reaches 20 to 30 cm
H2O. However, snorers and patients with OSA may not
arouse until esophageal pressures reach 40 to 80 cm H2O.
This implies a decrease in arousability (high arousal thresh-
old) in these groups.
Because esophageal pressure monitoring is infrequently
used, RERA detection is usually based on flattening of the
NP signal (flow limitation arousal).14,19 After arousal, there
is usually a sudden change in the NP contour from flat to
round (see Fig. 97). Ayappa and colleagues19 compared
arousal associated with flow limitation (FLA) and arousal
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126 Chapter 9 Monitoring RespirationEvent Definitions and Examples

Apnea duration Hypopnea duration

Nasal pressure

Nasal-oral
thermal sensor

Apnea or hypopnea duration is measured from the nadir preceding the first breath that is clearly
reduced to the beginning of the first breath that approximates the baseline breathing amplitude

FIGURE 95 Event duration rules. Note that the oronasal thermal sensor is used to define the apnea duration and the nasal pressure signal the hypopnea duration.

F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore 19 sec

NP

Airflow

Chest

Abdomen
SpO2
96%
1 sec

FIGURE 96 Respiratory effortrelated arousal (RERA). Flattening of nasal pressure for more than 10 seconds followed by an arousal. There is no
desaturation so it would not qualify as a hypopnea (by the recommended definition). The drop in flow is not 50% of baseline so the event would not qualify
as a hypopnea (alternative definition). ECG = electrocardiogram; NP = nasal pressure; SpO2 = pulse oximetry.

associated with increased respiratory effort by esophageal
manometry (RERAs). The FLA index and RERA index were
highly correlated (Fig. 98). However, a few FLA events
were noted with flow limitation but without an increase
in respiratory effort. Some RERAs (esophageal pressure
manometry) were noted without flow limitation. Thus,
although flow limitation (NP flattening) and high respiratory
effort most often occur together, this is not invariably true.
Fortunately, the majority of RERAs will be detected with NP
monitoring.
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 Chapter 9 Monitoring RespirationEvent Definitions and Examples 127

F4-M1
C4-M1
O2-M1
E1-M1
E2-M2
Chin
ECG
28 sec
Nasal pressure

Nasal-oral
thermal flow

Esophageal
pressure

Chest

Abdomen
SpO2
96% 95%

FIGURE 97 RERA. The event demonstrates increasing respiratory effort by esophageal pressure (slanted line) and flattening of the nasal pressure signal for longer
than 10 seconds followed by an arousal. After the event termination, there is a decrease in esophageal pressure excursions and the nasal pressure contour becomes
round. The event is not associated with a desaturation and is not a hypopnea by the recommended hypopnea scoring rule. The event also is not associated with a 50%
drop in the nasal pressure excursions. Therefore, the event is not a hypopnea using the alternative hypopnea scoring rule. ECG = electrocardiogram; SpO2 = pulse
oximetry.

Hypopnea or RERA?
Of note, if the recommended definition of hypopnea is used,
some obstructive events that would otherwise meet criteria
for the alternate definition of hypopnea would be scored as
RERAs. Such an event would be associated with an arousal
but not 4% or greater desaturation and have NP flattening
for 10 seconds or longer with drop in the excursions of the
NP signal by 50% or more from baseline (Fig. 99). Note that
part of the RERA definition is that the event does not meet
criteria for a hypopnea.
Relationship of Arousal and Respiratory Event
The AASM scoring manual did not specify a maximum time
interval from respiratory event termination until arousal ini-
tiation for the arousal to be considered respiratory. FAQ R19
states The scoring manual does not specify the time require-
ment linking arousals and respiratory event. When arousals
do occur with respiratory events, they usually occur within
5 seconds of airway opening. Arousals associated with respi-
ratory event termination can occur slightly before, concur-
rent with, or after event termination.20
Scoring Apneas and Hypopneas during Wake
In some cases, apneas and hypopneas may begin during an
epoch scored as sleep but end in an epoch scored as wake (or
vice versa). Scoring manual FAQ R10 states If any portion
of either the apnea or hypopnea occurs during an epoch
that is scored as sleep, then the corresponding respiratory
event can be scored and included in the computation of
the AHI. However, if the apnea or hypopnea occurs entirely
during an epoch scored as wake, it should not be scored or
counted toward the apnea-hypopnea index because of the
difficulty of defining a denominator in that situation.
Classification of Hypopneas
The AASM scoring manual recommends that hypopneas
not be classified (obstructive, central, or mixed) without a
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 128 Chapter 9 Monitoring RespirationEvent Definitions and Examples

30 quantitative assessment of ventilatory effort (esophageal

manometry, calibrated RIP, or diaphragmatic/intercostal
electromyography [EMG]). Of course, an accurate measure
RERAs by esophageal manometry (events/hr)

y
of airflow (PNT or NP) would also be needed. The AASM

tit
en
scoring manual did not provide definitions for hypopnea

Id
types. However, a possible scheme for defining types of
20 hypopneas is presented in Table 93 and Figure 910. One
can define an obstructive hypopnea as one due to an increase
in upper airway resistance (usually with increased respira-
tory effort). A central hypopnea would be due to a reduction
in respiratory effort with a proportionate decrease in airflow.
10
A mixed hypopnea would be characterized by both increased
upper airway resistance (NP flattening and airflow limita-
tion) and decreased respiratory effort (decreased esophageal
pressure excursions). In the absence of esophageal pressure
Asymptomatic monitoring, the shape of the NP tracing (or PNT) can
EDS/snoring provide some clues (see Table 93). The presence of a flat-
0 tened NP tracing, snoring, or chest-abdominal paradox sug-
0 10 20 30 gests airflow limitation (increased upper airway resistance),
Flow limitation events with arousal whereas a rounded shape without snoring is consistent with
by nasal cannula (events/hr) a lack of airflow limitation. Even with sophisticated monitor-
FIGURE 98 Flow limitation arousals and respiratory effortrelated arousals (RERAs) ing equipment, it may be difficult to precisely classify some
by esophageal monitoring (events/hour) were highly correlated, although not hypopneas.
identical. Reproduced from Ayappa I, Norman RG, Krieger AC, et al: Non-invasive
detection of respiratory effortrelated arousals (RERAs) by a nasal cannula/pressure
transducer system. Sleep 2000;23:763771. Chest-Abdominal Paradox
During normal inspiration, the rib cage expands and
the diaphragm contracts, moving the abdominal contents

F4-M1
C4-M1
O2-M1
E1-M1
E2-M2
Chin
ECG

20 sec
Nasal pressure

Nasal-oral
thermal flow
Chest

Abdomen

SpO2
92 92 93 93 93 93 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 95 95

FIGURE 99 RERA if the recommended hypopnea definition is used or hypopnea if the alternative hypopnea definition is used. Note that the 20 second arrow
is the duration of the 50% drop in NP excursions. However, the event duration as defined by the event duration rules would be longer (nadir preceding first breath
that is clearly reduced to the beginning of the first breath that approximates baseline breathing). The event duration would begin one breath earlier and end one
breath later than the 20 second line. ECG = electrocardiogram; SpO2 = pulse oximetry.
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 Chapter 9 Monitoring RespirationEvent Definitions and Examples 129

TABLE 93
Idealized Findings in Hypopnea
PNT/NP CHEST/ABDOMEN ESOPHAGEAL PRESSURE UPPER AIRWAY
TYPE AMPLITUDE/SHAPE DEFLECTIONS DEFLECTIONS RESISTANCE SNORE
Central Decreased amplitude Decreased Decreased Normal None
Round shape No paradox
Obstructive Decreased amplitude Variable Increased Increased Present
Flattened shape Paradox common Airflow limitation
Mixed Decreased amplitude Decreased Decreased Increased May be present
Flattened shape Paradox common Airflow limitation
NP = nasal pressure; PNT = pneumotachogram.

Central hypopnea

Airflow
(PNT)

Esophageal
pressure

Obstructive hypopnea

Airflow
(PTN)

Esophageal
pressure

Mixed hypopnea

Airflow
(PTN)

Esophageal
pressure

FIGURE 910 Examples of central, obstructive, and mixed hypopneas with an accurate measure of airflow (pneumotachograph [PNT]) and esophageal
pressure monitoring. In central and mixed hypopnea, the esophageal excursions decrease (up arrows). In mixed hypopnea, airflow limitation is present
(flattened airflow), and in central hypopnea, the airflow contour is round. In obstructive hypopnea, the esophageal pressure excursions are increased (black
circles) for at least part of the event.
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130 Chapter 9 Monitoring RespirationEvent Definitions and Examples

Snore

Nasal pressure

Nasal-oral
thermal flow

Chest
no P
P

Abdomen

96%

SpO2
88%
30 sec

FIGURE 911 An obstructive hypopnea with paradox (P) in chest and abdominal movement during the respiratory event but not during less obstructed breathing
(no P). SpO2 = pulse oximetry.

downward; the abdomen also moves outward. During chest-
abdomen paradox, the chest moves outward and the
abdomen inward or vice versa. Paradox is most helpful at
identifying high upper airway resistance when it is present
during the obstructive event and NOT present during unob-
structed breathing (Fig. 911; see also Fig. 94).
Conditions in which paradox may occur21:
1. Loss of diaphragm tone/weakness: The abdomen is sucked
inward as the rib cage expands during inspiration.
2. Loss of accessory muscle tone: Destabilizes the rib cage
so it may be sucked inward when the diaphragm contracts
(abdomen expands).
3. Partial upper airway obstruction: High pleural pressures
can overcome mechanisms maintaining rigidity of
thoraxparts are sucked inward. This is common in chil-
dren with more pliable chest walls.
4. Complete upper airway obstruction: The total volume of
respiratory system does not changewhen the abdomen
expands (diaphragm contracts) the chest volume must
decrease.
False Classification of Apneas as Central
As discussed in Chapter 8, even with RIP, an obstructive
apnea (by esophageal pressure manometry) may appear to
be a central apnea.22,23 In Figure 912, the RIP rib cage and
abdominal band tracings are nearly flat but persistent respi-
ratory effort is definitely noted in the esophageal pressure
tracing. Although misclassification of a few events is unlikely
to have major clinical consequences, proper adjustment
of chest and abdominal bands (position and tightness) is
crucial to avoid significant errors in event classification.
Computer software often adjusts sensitivity with an
autogain to avoid large breaths being off-scale. However,
this may decrease the gain so that small efforts are not rec-
ognized. In Figure 913, with an increase in the gain (size)
of chest and abdominal tracings, the event is clearly not a
central apnea.
Regarding central apneas, it is worth noting that the
upper airway can actually close during a central apnea.24 This
should not be surprising, considering the obstructive portion
of mixed apneas. Some have proposed that the observation
of cardiac oscillations in airflow tracings allows one to con-
clude that the upper airway is open (Fig. 914).25 However,
a study by Morrell and associates26 found that during
ventilator-induced central apneas in dogs, cardiac oscilla-
tions could be present in the flow tracings even if the airway
was noted to be closed by direct visualization. The appear-
ance of cardiac oscillations in the airflow tracings is rarely
noted in obstructive apnea. Therefore, the presence of cardiac
oscillations in the flow may be a clue that a central apnea is
present but one may not be able to infer that the upper
airway is indeed open.
Hypoventilation in Adults14
Hypoventilation during wakefulness is usually defined as an
arterial partial pressure of carbon dioxide (PaCO2) equal to
or greater than 45 mm Hg. During sleep, there may be
periods of time in which the SpO2 is reduced without associ-
ated events that meet criteria for apnea or hypopnea. Such
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 Chapter 9 Monitoring RespirationEvent Definitions and Examples 131

100
O2 Sat %
75
Contraction
50

PESOPH
10cm H2O

Sum (VT)
50 mL
5s
RC

Inspiration Expiration

ABD

FIGURE 912 An obstructive apnea appears to be a central apnea based on the rib cage (RC) and abdominal (ABD) respiratory inductance plethysmography
(RIP) tracings. The true nature of the event is shown by the persistent esophageal pressure (PESOPH) deflections. Data from Tobin MJ, Cohen MA, Sackner MA:
Breathing abnormalities during sleep. Arch Intern Med 1983;143:12211228.

Normal chest and abdomen gain High chest and abdomen gain

Nasal pressure

Nasal oral
thermal flow

Chest

Abdomen

SpO2
97 96 96 94 94 95 97 98 98 98 98 98 97 97 96 96 96 96 96 95 94 92 97 96 96 94 94 95 97 98 98 98 98 98 97 97 96 96 96 96 96 95 94

FIGURE 913 Left, The event may at first appear to be a central apnea. However, with an increase in gain in the chest and abdomen tracings, the obstructive nature of the event
is apparent. Right, The many small fluctuations in the chest and abdomen tracings are due to cardiac oscillations that are readily apparent only at the high gain. SpO2 = pulse
oximetry.

periods of arterial oxygen desaturation are sometimes
termed hypoventilation. However, this is presumptive
without direct measurement of PaCO2 or a surrogate. The
AASM scoring manual provides criteria for hypoventilation
during sleep and discourages use of the term hypoventila-
tion without documentation of an elevated PaCO2.
Hypoventilation Rule (AASM Scoring Manual14)
Score hypoventilation during sleep if there is a 10 mm Hg
increase in PaCO2 during sleep in comparison with an awake
supine value.
The AASM scoring manual also notes that persistent
oxygen desaturation in the absence of apnea or hypopnea is
not sufficient to document hypoventilation. It is observed
that finding an increase in the PaCO2 obtained immediately
upon awakening is suggestive of sleep hypoventilation. The
manual concluded that sufficient evidence was not available
to recommend a sensor to document hypoventilation. The
manual also states that both end-tidal carbon dioxide pres-
sure (PETCO2) and transcutaneous carbon dioxide pressure
(TcPCO2) may be used as surrogate measures of PaCO2 if
demonstrated to be reliable and valid.
Continuous arterial blood gas monitoring during PSG
is not practical (or well tolerated) and arterial blood gas
testing is most often performed at the start (to validate a
surrogate measure of PCO2) or on awakening often at study
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132 Chapter 9 Monitoring RespirationEvent Definitions and Examples
Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen
SpO2
FIGURE 914 A central apnea is seen with cardiac oscillations in the chest and airflow channels. The oscillations are also seen in the nasal pressure signal. There
is controversy about whether this means that the upper airway is open or closed. As discussed previously, the upper airway can close during central apnea.
SpO2 = pulse oximetry.
termination (to provide evidence for hypoventilation during
sleep). In children, an arterialized capillary blood gas rather
than an arterial sample is often performed.
The most common approaches to documenting hypoven-
tilation during sleep monitoring include measurement of
PETCO2 or TcPCO2. These methods are discussed in Chapter
8. Figure 915 presents a tracing from a patient with a neu-
romuscular disorder. The awake PETCO2 was 43 mm Hg, but
during sleep, the PETCO2 reached the mid 70s. As discussed
in Chapter 8, a PETCO2 tracing should show an alveolar
plateau to be accepted as an accurate estimate of the PaCO2.
In Figure 915, many of the breaths are not associated with
a good alveolar plateau. The last 2 breaths illustrate a desired
alveolar plateau. It should also be noted that the PaCO2
typically exceeds the PETCO2 by 4 to 6 mm Hg in normal
individuals. The difference can be increased in patients with
lung disease.
Cheyne-Stokes Breathing Rule14
Score Cheyne-Stokes breathing (CSB) if there are at least
three consecutive cycles of cyclic crescendo and decrescendo
change in breathing amplitude and at least one of the
following:
1. Five or more central apneas or hypopneas per hour of
sleep.
2. The cyclic crescendo and decrescendo change in breath-
ing amplitude has a duration of at least 10 consecutive
minutes.
CSB is characterized by central apnea or hypopnea at the
nadir of respiratory effort (Fig. 916) as well as an interven-
ing pattern of crescendo-decrescendo ventilation (flow or
tidal volume) between apneas/hypopneas. CSB is most com-
monly noted in patients with systolic congestive heart failure
(CHF) but can occur after stroke or with diastolic heart
failure. When CSB is associated with systolic CHF, a few
other characteristic PSG findings are of interest. First, the
cycle time (time from the onset of one apnea to the next
apnea) is usually approximately 50 to 60 seconds with long
ventilatory phases (crescendo-decrescendo) between the
central apneas.27 If associated arousals are present, they are
often at the zenith of respiratory effort. In addition, due to
low cardiac output, there is a long circulation time and the
nadir in desaturation is delayed relative to the event termina-
tion. Figure 917 presents a schematic showing the differ-
ences between central apnea in primary (idiopathic) central
apnea and CSB.
Respiratory Parameters Reported
in PSG (Adults)14,17
The following is a list of respiratory parameters that are rec-
ommended for presentation in a PSG report. Of note, the
RDI was not defined in the AASM scoring manual but is
added for completeness. Not all sleep centers report an RDI.
Two definitions of the RDI in common use are presented
here. The sleep study report should specify the RDI definition
(if reported) and the definition of hypopnea (recommended
or alternative) that was used for scoring the sleep study.
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 Chapter 9 Monitoring RespirationEvent Definitions and Examples 133

Nasal pressure

Airflow

Chest

Abdomen

SpO2
96 96 96 96 96 96 96 96 96 95 95 95

PETCO2
52 53 58 58 56 64 65 68 68 74 73 76

PCO2

FIGURE 915 Documentation of an increased partial pressure of carbon dioxide (PCO2) during sleep. Note the alveolar plateaus (black circles). PCO2 = exhaled
PCO2 waveform tracing; PETCO2 = most recent end-tidal reading; SpO2 = pulse oximetry.

60 sec

30 sec

Nasal pressure

Nasal-oral
thermal flow
Chest

Abdomen

95%
SpO2
82%

FIGURE 916 Cheyne-Stokes respiration with a crescendo-decrescendo pattern of respiration with central apneas at the nadir of effort. Note the nadir in the
pulse oximetry (SpO2) is very delayed following the end of the apneas. Top left corner, A tracing of Cheyne-Stokes breathing with a hypopnea at the nadir.

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134 Chapter 9 Monitoring RespirationEvent Definitions and Examples

FIGURE 917 Differences between Cheynes-Stokes breathing and

idiopathic (primary) central sleep apnea (CSA). SaO2 = arterial oxygen
saturation; SpO2 = pulse oximetry. CHEYNE-STOKES BREATHING
Cycle Length

Airflow

DS

SpO2

Idiopathic CSA

Cycle Length

Airflow

DS

SpO2

DS  Delay in SaO2 nadir

1. AH = number of apneas + number of hypopneas. respiration in children are very similar to those for monitor-
2. Number of obstructive, central, and mixed apneas. ing adults (Table 94). In children, it is very common for
3. Number of hypopneas. some respiratory sensors to fail during monitoring. For
4. AHI = number of apneas and hypopneas per hour of example, sensors might be pulled off by the child or the NP
sleep cannula may be dislodged or occluded with secretions.

60 AH / TST (total sleep time [min])

5. AHI during supine and nonsupine sleep.
6. AHI NREM and AHI rapid eye movement (REM).
7. OD = number of arterial oxygen desaturations.
8. Oxygen desaturation index (ODI) = (OD 60)/TST
(min).
9. Number of RERAs.
10. RERA index = (number of RERAs) 60/TST (min)
11. RDI
Definition #1 RDI = AHI
Definition #2 RDI = AHI + RERA index
RESPIRATORY EVENT SCORING RULES
IN CHILDREN
The AASM scoring manual provides separate rules for the
scoring of respiratory events in children. The rules are based
on a systematic review of the literature in children. Although
many of the rules are similar to those in adults, there are dif-
ferences. In children 13 years or older, the sleep specialist has
the option to use adult rules. The sensors for monitoring
Ages for Which Pediatric Scoring Rules
Should Be Used
Criteria for respiratory events during sleep for infants and
children can be used for children younger than 18 years. An
individual sleep specialist may choose to score children 13
years of age using adult criteria.
In adult patients, a 10-second breathing pause (minimum
apnea duration) is approximately 2 missed breaths (at a
respiratory rate of 12 breaths/min). In children, the respira-
tory rates are much faster and obstructive apneas shorter
than 10 seconds can have physiologic significance. Therefore,
the 2 missed breath rule is used for apneas in children. Short
central apneas are common in children and are often seen
after deep breaths (sighs) or arousals. Therefore, central
apneas must be longer (20 sec) or associated with physio-
logic significance to be scored. If a central apnea is greater
in duration than 2 missed breaths but less than 20 seconds,
it must be associated with arousal, desaturation, or awaken-
ing to be scored. The respiratory scoring rules for children
are listed in Table 94.
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 Chapter 9 Monitoring RespirationEvent Definitions and Examples 135

TABLE 94
Pediatric Respiratory Rules
Obstructive apnea Duration at least 2 missed breaths or equivalent duration.
>90% fall in signal for 90% of event duration.
Continued or increased inspiratory effort.
Event duration is from the end of last normal breath to the beginning of first breath achieving
baseline amplitude.
Mixed apnea Duration at least 2 breaths or equivalent duration.
>90% fall in signal for 90% of event duration.
Absent inspiratory effort in the initial portion of the event, followed by resumption of inspiratory
effort before the end of the event.
Central apnea Absent inspiratory effort.
Duration 20 sec.
OR
duration at least 2 missed breaths AND associated with arousal, awakening, or 3% desaturation.
Hypopnea NP signal falls by 50% from baseline.
Duration at least 2 missed breaths (or equivalent duration).
Fall lasts 90% of the event duration.
Arousal, awakening, or 3% desaturation occurs.
RERA All of the following in NP:
a. Discernible but <50% fall in signal.
b. Flattening of NP.
c. The event accompanied by snoring, noisy breathing, elevation in the end-tidal PCO2 or
transcutaneous PCO2, or increased WOB.
d. Duration at least 2 breath cycles.
All of the following when using esophageal pressure:
a. Progressive increase in respiratory effort.
b. Snoring, noisy breathing, increased end-tidal or transcutaneous PCO2, increased WOB.
c. Duration at least 2 breath cycles.
Hypoventilation 25% of the total sleep time with a PCO2 > 50 mm Hg. (PETCO2 or TcPCO2 are acceptable.)
Periodic breathing There are >3 episodes of central apnea lasting >3 sec separated by no more than 20 sec of normal
breathing.
NP = nasal pressure; PCO2 = partial pressure of carbon dioxide; PETCO2 = end-tidal carbon dioxide pressure; RERA = respiratory effortrelated arousal;
TcPCO2 = transcutaneous carbon dioxide pressure; WOB = work of breathing.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specifications, 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007.

Recommended Sensors in Children by AASM

Scoring Manual14
As in adults, the recommended sensor to score an apnea is an
oronasal thermal sensor. The alternative apnea sensors differ
somewhat from those in adults and include NP, exhaled CO2,
or the summed signal of calibrated RIP. The recommended
sensor for hypopnea is NP. The alternative sensor for hypop-
nea is a oronasal thermal sensor. Although not recommended,
one could use the RIPsum as well. For detection of respiratory
effort, recommended methods include esophageal manom-
etry and RIP (calibrated or uncalibrated). For alveolar
hypoventilation, acceptable signals are PETCO2 and TcPCO2.
1. Event lasts at least 2 breaths (or the duration of 2 breaths
as determined by baseline breathing pattern).
2. The event is associated with a >90% fall in the signal
amplitude for 90% of the entire respiratory event com-
pared with pre-event baseline amplitude.
3. The event is associated with continued or increased respi-
ratory effort throughout the entire period of decreased
airflow.
4. The duration of the apnea is measured from the end
of the last normal breath to the beginning of the first
breath that achieved the pre-event baseline inspiratory
excursions.

Apnea Rules for Children14 Mixed Apnea

Obstructive Apnea Score a respiratory event as a MIXED apnea if it meets both
Score an event as an OBSTRUCTIVE apnea if it meets all of criteria 1 and 2 for obstructive apnea, and it is associated
the following criteria: with absent inspiratory effort in the initial portion of the
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136 Chapter 9 Monitoring RespirationEvent Definitions and Examples

Snore

Nasal pressure

8 sec
Nasal-oral
thermal flow

Chest

Abdomen

98%
SpO2

93%

FIGURE 918 A short obstructive apnea in a 7-year-old child. There is a fall in the nasal-oral thermal flow of greater than 90% and continued inspiratory efforts
are noted. Even though the event duration is short, it was followed by an arterial oxygen desaturation. Of note, a desaturation is NOT necessary to score an obstructive
apnea. SpO2 = pulse oximetry.

Hypopnea Rule (Children)14

event followed by resumption of inspiratory effort before the
end of the event.
Central Apnea
Score a respiratory event as a CENTRAL apnea if it is associ-
ated with absent inspiratory effort throughout the entire
duration of the event and one of the following is met:
1. The event lasts 20 seconds or longer.
2. The event lasts 2 breaths (or the duration of 2 breaths as
determined by the baseline breathing pattern) AND is
associated with an arousal, an awakening, or a 3% or
greater desaturation.
An example of a short obstructive apnea (only 2 breaths
in duration based on thermal sensor) is shown in Figure
918. Examples of two possible central events are shown in
Figure 919. In the top event, there is an absence of airflow
with absent inspiratory effort. However, the duration is only
9 seconds and because it was not associated with an arousal
(following the event) or an arterial oxygen desaturation, it
would NOT be scored as a central apnea. The lower central
event meets criteria for scoring a central apnea.
The AASM scoring manual presents only a single hypop-
nea definition for children (versus the recommended and
alternative definitions in adults). The hypopnea definition
for children is similar to the alternative adult definition
except that the duration must be at least the equivalent of 2
missed breaths.
Score a hypopnea if all the following criteria are met:
1. The event is associated with a 50% fall in the amplitude
of the NP or alternative signal compared with the pre-
event baseline excursion.
2. The event lasts at least 2 missed breaths (or the duration
of 2 missed breaths as determined by baseline breathing
pattern) from the end of the last normal breathing
amplitude.
3. The fall in NP signal amplitude must last for 90% of the
entire respiratory event compared with the signal ampli-
tude preceding the event.
4. The event is associated with an arousal, awakening, or 3%
or greater desaturation.
The AASM scoring manual stated that if the NP signal is
not functioning, the oronasal thermal signal can be used to
score hypopnea.
RERA Rules for Children14
Score an RERA if the conditions in either 1 or 2 are met
(+ an arousal occurs):
1. Using a NP sensor, ALL must be met:
a. Discernible fall in amplitude of signal but it is less than
50% in comparison with baseline.
b. Flattening of NP waveform.
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 Chapter 9 Monitoring RespirationEvent Definitions and Examples 137

Nasal pressure

Nasal-oral
thermal flow 11 sec

Chest

Abdomen

SpO2
94 94 95 94 94 94 95 95 96 96 97 98 98 99 99 99

16 sec

Nasal pressure

Nasal-oral
thermal flow

Chest

Abdomen

SpO2
98 98 98 98 98 98 98 98 98 98 97 95 94 94 93 91 91

FIGURE 919 A respiratory event in a 6-year-old child. The upper central event would not be scored as a central apnea because the duration is less than 20 seconds
and there is no associated arousal or desaturation. The bottom central event would be scored as a central apnea because it is longer than 2 missed breath cycles
and is associated with an arterial oxygen desaturation. SpO2 = pulse oximetry.

c. The event is accompanied by snoring, noisy breathing,

elevation in PETCO2 or TcPCO2, or visual evidence of Hypoventilation Rule for Children14
increased work of breathing.
Score the presence of sleep-related hypoventilation
d. The duration of the event is at least 2 breath cycles (or
when 25% of the total sleep time as measured by
duration of 2 breath cycles as determined by baseline
the TcPCO2 and/or the PETCO2 is spent with a PaCO2
breathing pattern).
>50 mm Hg.
2. Using an esophageal pressure sensor. ALL must be met:
The AASM scoring manual noted that the PETCO2
a. Progressive increase in inspiratory effort during the
signal often malfunctions (dislodged or occluded with nasal
event.
secretions) during pediatric PSG or provides falsely low
b. The event is accompanied by snoring, noisy breathing,
values in patients who have marked nasal obstruction, are
elevation in PETCO2 or TcPCO2, or visual evidence of
obligate mouth breathers, or are receiving either supple-
increased work of breathing.
mental oxygen or CPAP during the PSG. As previously
c. The duration of the event is at least 2 breath cycles (or
noted, it is essential to obtain an alveolar plateau in the
duration of 2 breath cycles as determined by baseline
PCO2 signal for the PETCO2 value to be considered valid. As
breathing pattern).
discussed earlier, the TcPCO2 value is good for illustrated
The AASM scoring manual stated that an RERA cannot trends in PaCO2 but a time lag in change in the TcPCO2
be scored without an adequate NP or esophageal manometry values is noted after acute changes in respirations (slow
signal. response time).
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138 Chapter 9 Monitoring RespirationEvent Definitions and Examples

Snore

Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen

SpO2
93%
Exhaled 50
PCO2 0

FIGURE 920 Obstructive hypoventilation. The end-tidal partial pressure of carbon dioxide (PCO2) is greater than 50 mm Hg and there is evidence of snoring
and flattening of the nasal pressure. A very mild drop in the pulse oximetry (SpO2) is noted.

Nasal pressure

CO2

Chest

Abdomen

SpO2
98 92 98 95 93 96 98

10 sec

FIGURE 921 Periodic breathing in a newborn infant (43 wk conceptual age). Note the lag in the end-tidal PCO2 tracing (CO2) compared with the nasal pressure
tracing. SpO2 = pulse oximetry.

Obstructive Hypoventilation Respiratory Parameters Reported

Obstructive hypoventilation29,30 is a term used to describe the
periods during which there is evidence of hypoventilation
(increased PETCO2) without discrete events but associated
with evidence of upper airway narrowing (snoring, NP flat-
tening, chest-abdominal paradox). Figure 920 presents an
example of obstructive hypoventilation in a 6-year-old child.
Although this term is not specifically defined in the AASM
scoring manual, it is widely used.
Periodic Breathing Rule for Children14
Score periodic breathing if there are more than three epi-
sodes of central apnea that last longer than 3 seconds sepa-
rated by no more than 20 seconds of normal breathing.
Figure 921 presents a 60-second tracing from a newborn
term infant. The central apneas are longer than 3 seconds,
there are more than three central apneas, and the breathing
between the central apneas is less than 20 seconds. This
meets criteria for periodic breathing. This is a normal breath-
ing pattern in preterm and term infants.
in PSG (Children)
Many sleep centers report respiratory events in children
somewhat differently than those in adults. The differences
include reporting the central AHI and obstructive AHI sepa-
rately and reporting data concerning the PETCO2 and/or
TcPCO2. Specifically, the maximum PETCO2 and time spent
greater than 50 mm Hg (absolute time or as % TST) are typi-
cally reported. Not all sleep centers report an RDI. The RDI
should be defined if included in the report.
1. A + H = number (#) of apneas + number of
hypopneas.
2. Number of obstructive apneas, central apneas, mixed
apneas, and hypopneas.
3. AHI = number of apneas and hypopneas/hr of sleep
60 AH / TST (min)
4. Obstructive AHI = (# obstructive apneas + # mixed
apneas + # hypopneas) 60/TST (min).
5. Central AHI = number of central apneas 60/TST (min).
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 Chapter 9 Monitoring RespirationEvent Definitions and Examples 139

6. AHI during supine and nonsupine sleep. A. PaCO2 50 mm Hg for 10% of total sleep time.
7. AHI NREM and AHI REM. B. PaCO2 > 50 mm Hg for 25% of total sleep time.
8. OD = number of arterial oxygen desaturations. C. PaCO2 50 mm Hg for 25% of total sleep time.
9. ODI = (OD 60)/TST (min).
D. PaCO2 < 55 mm Hg for 25% of total sleep time.
10. # RERA = number of RERAs.
11. RERA index = number of RERAs 60/TST (min). 4. At what age and above can adult scoring rules be used at
12. RDI the discretion of the clinician?
Definition #1 RDI = AHI
A. 12 years.
Definition #2 RDI = AHI + RERA index
13. Time with PETCO2 or TcPCO2 greater than 50 mm Hg B. 13 years.
(as total minutes or as % TST). C. 14 years.
D. 16 years.
CLINICAL REVIEW QUESTIONS 5. According to the AASM scoring manual, score periodic
1. Hypoventilation during wakefulness for adults is defined breathing in children if:
as a PaCO2 45 mm Hg. Hypoventilation during sleep is A. >3 episodes, central apnea lasting >3 seconds,
defined as: separated by no more than 20 seconds.
A. PaCO2 5 mm Hg above an awake supine value. B. >3 episodes, central apnea lasting >3 seconds,
B. PaCO2 10 mm Hg above an awake supine value. separated by no more than 10 seconds.
C. PETCO2 5 mm Hg above the wake value. C. >3 episodes, central apnea lasting >2 seconds,
separated by no more than 20 seconds.
D. PETCO2 10 mm Hg above the wake value.
D. >3 episodes, central apnea lasting >5 seconds,
2. In the table, which group (A, B, C, or D) is correct for separate by no more than 20 seconds.
recommended and alternate definitions of hypopnea in
adults and hypopnea in children? NP = nasal pressure Answers
excursions.
1. B. The AASM scoring manual defines hypoventilation
CHANGE IN NP based on the arterial PaCO2 of 10 mm Hg above the
FROM BASELINE DESATURATION waking value. The PETCO2 or TcPCO2 can be used to
A. Adult hypopnea Drop of 30% 4% define hypoventilation only when it has been validated as
(recommended) an estimate of the patients ventilation.
Adult hypopnea Drop of 30% 4% (or arousal) 2. D
(alternate)
Child hypopnea Drop of 50% 3% (or arousal) 3. B
B. Adult hypopnea Drop of 30% 4% 4. B
(recommended)
Adult hypopnea Drop of 50% 3% (or arousal)
5. A
(alternate)
Child hypopnea Drop of 30% 3% (or arousal)
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of Sleep Medicine, 2007.
15. Redline S, Budhiraja R, Kapur V, et al: The scoring of respira-
tory events in sleep: reliability and validity. J Clin Sleep Med
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AASM criteria for scoring hypopneas: impact on the apnea
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meters for the indications for polysomnography and related
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763771.
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Sleep and Respiratory
Physiology
Chapter Points
Mechanisms of hypoxemia include high altitude,
hypoventilation, V Q  mismatch, and shunt.
If hypoxemia is due to hypoventilation alone, the A-a
gradient [alveolar PO2 (PAO2) arterial PO2 (PaO2)] is
normal.
Alveolar hypoventilation with a normal A-a gradient
suggests that a disorder of ventilatory control or
respiratory muscle strength is present.
Patients with alveolar hypoventilation due to
parenchymal lung disease have an increased A-a
gradient (usually >25).
The PaCO2 = constant [CO2 production/alveolar
ventilation]. If everything else remains the same, a 50%
decrease in alveolar ventilation causes a doubling of
the PaCO2.
For a given minute ventilation (tidal volume
respiratory rate), the alveolar ventilation is lower with
a pattern of higher respiratory rate and smaller tidal
volume.
Increases in the dead spacetotidal volume ratio
(VD/V T ) from a high VD and/or a low V T reduce the
alveolar ventilation for a given minute ventilation.
OVD is characterized by a reduced FEV1/FVC and
normal or increased lung volumes (TLC, FRC, RV). If
the VC is reduced, this is secondary to a high RV.
RVD is characterized by a normal FEV1/FVC ratio and a
reduced VC and TLC.
The most common pulmonary function test
abnormality in patients with simple obesity is a
reduced ERV (low FRC relative to the RV).
Muscle weakness can cause RVD but must be fairly
severe (MIP < 60 cm H2O).
An increased serum HCO3 is a clue that chronic
hypoventilation may be present (especially if
>27 mEq/L).
The hydrogen ion concentration (pH) is determined by
the ratio PaCO2/HCO3. Compensatory mechanisms
attempt to normalize the ratio.
Chapter 10
The goal of this chapter is to present a brief overview of
aspects of respiratory physiology useful for the sleep physi-
cian. Most patients who have arterial oxygen desaturation
in the sleep center do so from apnea or hypopnea. However,
patients with respiratory disorders may have sleep-related
arterial oxygen desaturation and/or hypoventilation without
a significant number of discrete apnea or hypopnea events.
These abnormalities in gas exchange can occur because the
normal effects of sleep on ventilation and oxygenation are
magnified by abnormal function of the lung, chest wall,
respiratory muscles, or ventilatory control centers. The
effects of lung disease on breathing during sleep are dis-
cussed in more detail in Chapters 21 and 22.
ARTERIAL BLOOD GASES
Alveolar hypoventilation during wakefulness is defined as an
arterial partial pressure of carbon dioxide (PaCO2) of
45 mm Hg or higher. If the sleeping PaCO2 is 10 mm Hg
above the awake value, nocturnal hypoventilation is said to
be present. Hypoxemia is defined as a low arterial partial
pressure of oxygen (PaO2) relative to predicted values. A
PaO2 less than 55 mm Hg while breathing room air is con-
sidered severe and an indication for chronic 24-hour supple-
mental oxygen therapy. Milder degree of hypoxemia can be
identified by comparing a PaO2 with a predicted value for
age. A simple estimate of a normal predicted PaO2 is 105 1 2
age (yr).
The alveolar gas equation1 (Equation 101) allows one to
compute the alveolar (ideal) partial pressure of oxygen
(PAO2) from the fractional concentration of oxygen in
inspired gas (FIO2), which is 0.21 when breathing room air,
and the PaCO2. The respiratory exchange ratio (R) is the CO2
elimination divided by the O2 uptake. At steady state, R is
equal to the respiratory quotient (RQ), which equals the CO2
production/O2 consumption ( VCO  
2 VO2). R is usually
assumed to be 0.8.1 In Equation 101, FIO2 = 0.21 (breathing
room air), PB is the barometric pressure (760 mm Hg at sea
level), and PH2O is the partial pressure of water vapor
(47 mm Hg at 37C).
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142 Chapter 10 Sleep and Respiratory Physiology
Computation of the PAO 2 and the A-a gradient
PAO2 = FIO2 ( PB PH2O ) PaCO2 /R
R = VCO 
2 /VO2 ( assumed to be 0.8 )
VCO 
2 = CO2 elimination VO2 = O2 uptake
Equation 101
Breathing room air, Equation 101 becomes Equation 102.
The A-a gradient (Equation 103) is the difference between
the ideal PAO2 and the actual (measured) PaO2. Equation
104 gives the predicted A-a gradient (usually <25 mm Hg).
(room air ) PAO2 = 0.21(760 47 ) PaCO2 /0.8
= 150 PaCO2 /0.8
A-a gradient = PAO2 PaO2
Predicted estimate of normal A-a gradient = 4 + age (yr )/4
For example, for a 48-year-old, A-a gradient = 16
Equation 104
The major causes of hypoxemia are listed in Table 101.
Causes of hypoxemia include a low FIO2, a low PB (high
altitude), hypoventilation (increased PaCO2), and incom-
plete oxygenation of the blood by the lung (ventilation-
 mismatch or shunt). In V Q
perfusion [ V Q]  mismatch,
some alveoli are underventilated for their blood flow (low
 and blood is incompletely oxygenated. This can be
V Q)
overcome by increasing the FIO2, thereby increasing the
effective oxygen flow to underventilated alveoli. If shunt is
causing hypoxemia, blood completely bypasses the alveoli.
The deoxygenated blood mixes with oxygenated blood to
give a lower than ideal PaO2. Raising the FIO2 has no effect
on shunted blood. Most patients with lung disease also have
defects in CO2 excretion. This may not result in alveolar
hypoventilation because the patient may compensate by
increasing the minute ventilation (discussed later).
Hypoxemia can occur simply as a consequence of
hypoventilation. For example, a patient with normal lungs
may have an increased PaCO2 due to muscle weakness or
abnormal ventilatory control. In this case, the PaO2 is fairly
close to the ideal (PAO2) computed from the alveolar gas
TABLE 101
Major Causes of Hypoxemia
RESPONDS TO
A-a SUPPLEMENTAL
GRADIENT OXYGEN
Low FIO2, low PB Normal Yes
Hypoventilation Normal Yes
 mismatch
V Q Increased Yes
Shunt Increased No
A-a = alveolar-arterial; FIO2 = fractional concentration of oxygen in inspired
gas; PB = barometric pressure; V Q  = ventilation-perfusion (ratio).
equation (Equation 101) using the known PaCO2. The A-a
gradient (Equation 103) in such patients is normal. Lung
disease severe enough to cause an increased PaCO2 is always
associated with an increased A-a gradient.
Box 101 presents examples of use of the alveolar gas
equation (Equation 101). In a patient with amyotrophic
lateral sclerosis (ALS; Example 1), an arterial blood gas
reveals a PaO2 of 60 and PaCO2 of 65 mm Hg. The computed
A-a gradient is 8.7 mm Hg (normal). Hypoxemia is due to
hypoventilation. In Example 2, a patient with chronic
obstructive pulmonary disease has evidence of both hypox-
emia and hypercapnia and the A-a gradient is increased. The
 mismatch and hypoventila-
hypoxemia is due to both V Q
tion. In patients with hypoventilation of unclear etiology,
Equation 102 calculating an A-a gradient can provide an important clue as
Equation 103 to whether the hypoventilation is due to lung disease or due
totally to hypoventilation. A normal A-a gradient in a patient
with hypoventilation would suggest a disorder of ventilatory
control or muscle weakness.
OXYGEN TRANSPORT AND SATURATION
The majority of the oxygen-carrying capacity of the blood is
due to oxygen bound to hemoglobin (Hb) with a small frac-
tion of dissolved oxygen (Equation 105).1 When fully satu-
rated, a gram of Hb carries about 1.34 mL/dL of oxygen
(1 dL = 100 mL).
Oxygen content of arterial blood (CaO2 [mL O2/100 mL])
CaO2 = 1.34 mL/g Hb ( g/100 mL ) SaO2 + 0.003 PaO2
Equation 105
BOX 101
Examples of Computation of the Alveolar Partial
Pressure of Oxygen and the A-a Gradient
EXAMPLE 1: HYPOVENTILATION DUE TO AMYOTROPHIC
LATERAL SCLEROSIS (NORMAL A-a GRADIENT)
Laboratory: PaO2 = 60 mm Hg and PaCO2 = 65 mm Hg
(breathing room air)
PAO2 = 150 65/ 0.8 = 68.7
A-a gradient = PAO2 PaO2 = 68.7 60 = 8.7 ( normal)
EXAMPLE 2: HYPOVENTILATION DUE TO CHRONIC
OBSTRUCTIVE PULMONARY DISEASE (INCREASED A-a
GRADIENT)
Laboratory: PaO2 = 50 mm Hg and PaCO2 = 55 mm Hg
PAO2 = 150 55/ 0.8 = 81
A-a gradient = PAO2 PaO2 = 81 50 = 31 ( increased )
A-a = alveolar-arterial; PaCO2 = arterial partial pressure of
carbon dioxide; PAO2 = alveolar partial pressure of oxygen;
PaO2 = arterial partial pressure of oxygen.
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 Chapter 10 Sleep and Respiratory Physiology 143

SHIFT TO LEFT
Temperature
PaCO2
Hydrogen ion HIGHER PaO2 WITH RIGHT SHIFT
concentration
100 2,3-DPG 100

% Oxygen saturation (SaO2)

% Oxygen saturation (SaO2)

80 80

Shift to right
60 60
Temperature
PaCO2
40 Hydrogen ion 40
concentration
20 2,3 DPG 20

0 0
0 20 40 60 80 100 0 20 40 60 80 100
PaO2 (mm Hg) PaO2 (mm Hg)
Oxyhemoglobin dissociation curve Oxyhemoglobin dissociation curve

FIGURE 101 Left, The shift in the oxygen hemoglobin dissociation curve left or right depends on the illustrated factors.
Right, A shift to the right increases the arterial partial pressure of oxygen (PaO2) for a given arterial oxygen saturation (SaO2).
2,3-DPG = 2,3-diphosphoglycerate; PaCO2 = arterial partial pressure of carbon dioxide.

SaO2 = 100 O2 Hb/(O2 Hb + RHb) Equation 106 Hb A

100
The arterial oxygen saturation (SaO2) is usually expressed as 90 Hb S
the ratio of oxygenated hemoglobin (O2Hb) to the total 80
Oxygen saturation (%)

amount of Hb that can bind oxygen (Equation 106). The 70

amount of hemoglobin that can bind oxygen is the sum of 60
O2Hb and deoxygenated (reduced) hemoglobin (RHb). The 50
SaO2 value for a given PaO2 depends on the position of 40
the oxygen-hemoglobin saturation curve (also called the 30
oxygen-hemoglobin dissociation curve)1 (Fig. 101). At the 20
usual body temperature and pH, a PaO2 of 60 mm Hg cor- 10
responds to approximately an SaO2 of 90%. A left shift results 0
in a lower PaO2 being associated with a given SaO2 and vice 0 10 20 30 40 50 60 70 80 90 100
versa. A shift to the left can occur with decreasing tempera- PaO2 (mmHg)
ture, hydrogen ion concentration [H+], PaCO2, or level of FIGURE 102 A patient with sickle hemoglobin (Hb S) will have a higher arterial
2,3-diphosphoglycerate (2,3-DPG). Abnormal Hbs can also partial pressure of oxygen (PaO2) associated with a given SaO2. Hb A = hemoglobin A.
result in a different relationship between the SaO2 and the
PaO2. For example, in patients with sickle cell disease (SCD),
TABLE 102
the PaO2 for a given SaO2 is higher due to the rightward shift
Typical SaO2 Values for Given PaO2
of the O2Hb saturation curve for hemoglobin S (HbS) com-
(Assumes Normal pH)
pared with hemoglobin A (HbA).2 The position of the O2Hb
dissociation curve is often defined by the P50, which is the PaO2 (MM HG) SaO2 (%)
PaO2 corresponding to an SaO2 of 50%. For HbA, the P50 is 30 60
26 mm Hg but is 42 to 56 mm Hg in SCD patients.2 The net
effect is a rightward shift in the O2Hb dissociation curve for 40 75
HbS. This means that for a given SaO2, the PaO2 is higher in 60 90
SCD patients than would be expected based on the normal PaO2 = arterial partial pressure of oxygen; SaO2 = arterial oxygen saturation.
O2Hb dissociation curve. The amount of right shift varies
considerably between SCD patients and can be influenced by
transfusion with blood (HbA) (Fig. 102). studies by pulse oximetry3 (SpO2) to detect arterial oxygen
Table 102 presents some useful PaO2 and associated desaturation and hypoxemia.
saturations. For PaO2 values of 30, 40, and 60 mm Hg, the At normal PaO2 levels, only a small amount of oxygen is
corresponding SaO2 is 60%, 75%, and 90% values, respec- dissolved in the blood and most of the oxygen-carrying
tively. The SaO2 is measured noninvasively during sleep capacity depends on the amount of Hb bound to oxygen.
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144 Chapter 10 Sleep and Respiratory Physiology
HEMOGLOBIN EXTINCTION CURVES
10
660 nm 940 nm
Extinction coefficient
1 R Hb
O2Hb
.1
COHb
.01
600 640 680 720 760 800 840 880 920 960
A Wavelength (nm)
FIGURE 103 A, Hemoglobin extinction curves for reduced hemoglobin (R Hb), oxyhemoglobin (O2Hb), and carboxyhemoglobin
(COHb) at different wavelengths of light. Note that the y axis is a log scale. B, Empirical curve of the ratio of absorption of radiation
(R) at wavelengths of 660 and 940 nm. AC = pulse added absorption; DC = steady state or background absorbance; SpO2 = pulse
oximetry. A and B, Adapted from Temper KK, Barker SJ: Pulse oximetry. Anesthesiology 1989;70:98108.
However, determining the oxygen-carrying capacity of Hb is
complicated by the fact that both carboxyhemoglobin
(COHb) and methemoglobin (MetHb) are forms of circulat-
ing Hb that do not bind oxygen. Carboxyhemoglobin occurs
when carbon monoxide (CO) binds to Hb. Smokers have
increased carboxyhemoglobin. MetHb occurs when the
normal ferrous state (Fe2+) of the iron moiety in Hb is oxi-
dized to the ferric stage (Fe3+). Significant methemoglobin-
emia can occur after exposure to certain medications but is
uncommon in the sleep center. The sum of the fractional
concentrations of O2Hb, RHb, COHb, and MetHb equal
100% (Equation 107). The true fraction of hemoglobin
bound to oxygen (FO2Hb) is given by Equation 108 and
depends on the fraction (%) of carboxyhemoglobin (FCOHb)
and methemoglobin (FMetHb) as well as the fraction of
reduced hemoglobin (FRHb).46
FO2 Hb + FRHb + FCOHb + FMetHb = 100%
Equation 107
or
FO2 Hb = O2 Hb 100/ ( O2 Hb + RHb + COHb + MetHb )
FO2 Hb = O2 Hb 100/Hbt
Equation 108
where O2Hb, RHb, COHb, and MetHb are the concentra-
tions of the types of Hb and equal the total Hb concentration
(Hbt). For example, if the FO2Hb = 85%, FCOHb = 8%,
FmetHb = 1%, then the FRHb is 6%. Using these numbers
and Equation 103, the SaO2 equals 85 100/(85 + 6) or
93%, which is considerably higher than FO2Hb of 85%. The
FO2Hb and the amount of Hb are the main determinants of
the bloods oxygen-carrying capacity. When significant
COHb or MetHb is present, Equation 105 should have SaO2
replaced by FO2Hb. The difference between the SaO2 and the
FO2Hb (in %) at normal PO2 values is approximately equal
to the sum of FCOHb and FMetHb.4 The FO2Hb is some-
times called the fractional saturation and the SaO2 the func-
tional or effective saturation. Of note, the PaO2 depends on
100
90
80
70
SpO2 (%)
60
50
40
30
20
10
0.4 1.0 2.0 3.0
R
AC660 /DC660
R
B AC940 /DC940
the SaO2, not the FO2Hb. That is, the oxyhemoglobin satura-
tion curve expresses the ratio of oxygenated Hb to the total
Hb available for oxygen binding. Neither COHb nor MetHb
binds oxygen. However, the position of the oxyhemoglobin
saturation curve is shifted to the left by the presence of
COHb or MetHb.4,7
The previous four fractions of Hb can be accurately mea-
sured by co-oximeters that measure the absorption of 4 or
more wavelengths of electromagnetic radiation by blood.1,5
This is possible because the four forms of Hb differ in their
absorption for the different wavelengths of radiation. In con-
trast, pulse oximetry3 uses only two wavelengths: 660 nm
(red) and 940 nm (infrared) to measure the O2Hb and RHb.
The absorption of radiation at 660 nm is much greater with
RHb than O2Hb, whereas O2Hb absorbs more radiation at
940 nm (Fig. 103A). SpO2 is based on the empirical obser-
vation that the ratio (R) of absorbance at the 2 wavelengths
is related to the oxygen saturation (see Fig. 103B). This
relationship (calibration curve) is calculated experimentally
by determining R at varying oxygen saturations. To specifi-
cally determine the absorbance of arterial blood, the AC
(pulse added absorbance) at each wavelength is divided by
the DC (background absorbance) to account for the effect of
the absorption of the radiation by venous blood and tissue.
COHb has about the same absorbance at 660 as O2Hb and,
if present, increases the measured SpO2 value. In normal
individuals, FCOHb is 2% or less but can be 8% or more in
cigarette smokers. Patients with SCD often have FCOHb
values of 4% or more due to production of CO from chronic
hemolysis. Based on a canine experiment,3 it has been esti-
mated that a pulse oximeter sees COHb as 90% O2Hb and
10% RHb. For example, from the values FO2Hb = 85%,
COHb = 4%, MetHb = 0%, RHb = 11%, one can estimate the
SpO2 as 88.6% (85 + 0.9 4). This is essentially the same as
the SaO2 computed from Equation 102 for these values.
Thus, the SpO2 is a much better estimate of the SaO2 than
the FO2Hb is. In patients who are heavy smokers, it is impor-
tant to remember that the SpO2 may overestimate the FO2Hb.
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 Chapter 10 Sleep and Respiratory Physiology 145

TABLE 103
Different Patterns of Breathing with Changing Dead Space and Tidal Volume
ALVEOLAR
VD VT RR MV VENTILATION PACO2
VD/V T (ML) (ML) (BPM) (L/MIN) (L/MIN) (MM HG)
A Normal 0.3 200 600 10 6.0 4.0 40
B Low V T, same MV 0.5 200 400 15 6.0 3.0 53
C High VD 0.42 300 700 10 7.8 4.0 40
D High VD, low V T 0.75 300 500 20 10.0 4.0 40
Notes:
B. Low V T; even with higher RR and similar MV, the alveolar ventilation is decreased.
C. High VD is compensated by an increase in V T; with a higher MV, a normal alveolar ventilation is obtained.
D. High VD, low V T results require much higher MV to achieve a normal alveolar ventilation.
PaCO2 = K VCO 2 / (RR VT )(1 VD /VT )
Assume K VCO
2 = 160

K = constant = 0.863; MV = minute ventilation; PaCO2 = arterial partial pressure of carbon dioxide; RR = respiratory rate; VCO 2 = carbon dioxide production;
VD = dead space; V T = tidal volume.

If a patient has a lower than expected SpO2 while awake 

in the sleep center, a number of possibilities should be con-
sidered including a faulty oximetry probe, poor signal quality
due to poor perfusion, a shift in the O2Hb saturation curve
due to the factors illustrated in Figure 101 or an abnormal
Hb. If oximetry issues are ruled out, an arterial blood gas is
needed to determine whether hypoxemia is really present. In
this situation, co-oximetry analysis could also determine
whether significant COHb or MetHb is present and deter-
mine a true SaO2 and the fraction of Hb that is oxygenated.
Sometimes, the SaO2 reported with an arterial blood gas is
simply determined from the measured PaO2 and a nomo-
gram. If clinically indicated, analysis with a co-oximeter will
provide more accurate information.
DETERMINANTS OF PaCO2
The PaCO2 is related to the VCO  2 and the alveolar ventila-
tion ( V A ) (Equation 109). For a given VCO  
2 , if the VA
doubles, the PaCO2 decreases by half. The PaCO2 will
increase if the V A decreases or the VCO  2 increases (Equa-
tion 109). The V A equals the minute ventilation (V  E) minus
the dead space ventilation (V D). The V D is wasted ventila-
 E = the respiratory rate (RR) tidal volume (VT)
tion. The V
(Equation 10-10). The V  D can be written as the product of
the RR and the dead space (VD). The dead space includes the
anatomic dead space (no alveoli) and overventilated areas of
the lung (high V Q  units). The equation for PaCO2 can be
written so that PaCO2 depends on the minute ventilation (VT
RR) and the VD/VT ratio (Equation 1011).
VCO 2
PaCO2 = K
VA Equation 109
K = constant
A = V
V E V
D Equation 1010
= RR VT RR VD
VCO
K 2
Equation 1011
RR VT (1 VD VT )
K = constant
For the same minute ventilation, breathing with a low VT
and high RR increases the VD/VT ratio, decreases the V  A , and
increases the PaCO2 (Table 103). The normal VD/VT ratio
in % is 24.6 + 0.17 age (yr). For example, a 40-year-old
individual would have a VD/VT of about 31% or a ratio of
0.31. The anatomic VD is approximately equal to a persons
weight in pounds. The physiologic VD equals the anatomic
VD + the effect of high V Q lung units. In lung disease, the
physiologic VD is increased and higher than normal minute
ventilation is needed to produce the same alveolar ventila-
tion (and PaCO2). Patients who have a rapid shallow breath-
ing pattern are predisposed to hypoventilation because this
is an inefficient method of breathing. However, patients with
muscle weakness or a stiff chest wall (high work of breath-
ing) may utilize a pattern of ventilation with a small VT and
high RR to avoid respiratory muscle fatigue.
NORMAL CHANGES IN
VENTILATION DURING SLEEP
The changes in arterial blood gases during normal sleep are
summarized in Figure 104. During sleep, the metabolic rate
falls (hence, decreased CO2 production), but this is offset by
a proportionately greater fall in minute ventilation with the
result that the PaCO2 increases slightly. The fall in ventilation
is due to increased upper airway resistance and decreased
chemosensitivity as well as the loss of the wakefulness stimu-
lus to breathe.811 The result is that the PaCO2 rises and the
PaO2 falls slightly.
Because of the normal position on the flat portion of the
O2Hb dissociation curve, there is little change in the SaO2 as
a result of the fall in PO2 associated with sleep (Fig. 105).
If the baseline awake PaO2 is lower, the fall in SaO2 will be
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146 Chapter 10 Sleep and Respiratory Physiology

Loss of 10 mm Hg decrease in PaO2

wakefulness Metabolic rate causes a greater desaturation
stimulus decreases 10-15% starting on the steeper part of
the curve
100
Upper
Ventilation Chemosensitivity
airway

% Oxygen saturation (SaO2)

0.5 - 1.5 L/min 20-50% 80
resistance

60
PaCO2 2-8 mm Hg
PaO2 3-10 mm Hg
SaO2 1-2% 40

FIGURE 104 Changes in ventilation and gas exchange with normal sleep. The loss of
wakefulness stimuli and reduced ventilatory drive + increased upper airway resistance 20
result in a reduction in minute ventilation. Although the metabolic rate and CO2
excretion are lower, the net effect is a mild increase in the arterial partial pressure of 0
carbon dioxide (PaCO2) and decrease in the arterial pressure of oxygen (PaO2). SaO2 = 20 40 60 80 100
arterial oxygen saturation. From Mohsenin V: Sleep in chronic obstructive pulmonary PaO2 (mm Hg)
disease: sleep and respiration. Semin Respir Crit Care Med 2005;26:109115. Oxygen-hemoglobin saturation curve

FIGURE 105 The same drop in arterial partial pressure of oxygen (PaO2) causes a
greater drop in the arterial oxygen saturation (SaO2) if the starting point is on the steeper
slope of the oxygen-hemoglobin saturation curve.

110 110

100 100
Percent

Percent

90 90

80 80

W St. 2 St. 3-4 REM W St. 2 St. 3-4 REM

Tidal volume Respiratory rate

FIGURE 106 The fall in minute ventilation with sleep is due to a fall in tidal volume (VT) with no significant change
in respiratory rate (RR). REM = rapid eye movement; St. 2 = stage N2; St. 3-4 = stage 3-4 (stage N3); W = wake. From
Krieger J: Respiratory physiology: breathing in normal subjects. In Kryger MH, Roth T, Dements WC (eds): Principles and
Practice of Sleep Medicine. Philadelphia: Elsevier, 2005, pp. 232255.

greater for the same drop in PaO2. In patients with lung

disease and a lower awake PO2, even a normal sleep-related
drop in PO2 will be associated with a larger decrease in the
SaO2.
The change in ventilation with sleep is due to a fall in VT
with minimal change in the RR9 (Fig. 106). During the
transition from wake to stage N1 and early stage N2, the
ventilation can be slightly irregular. However, in stable stage
N2 and stage N3, the VT and RR are nearly constant. During
rapid eye movement (REM) sleep, ventilation is irregular
with periods of decreased VT associated with bursts of eye
movements.12 The FRC decreases from wake to sleep.13 In
some individuals, there may be a further decrease from non
rapid eye movement (NREM) to REM sleep.14
TESTS OF VENTILATORY CONTROL
The major chemoreceptors are the carotid body (responding
to PaO2 and PaCO2) and the medullary chemoreceptors
(responding to changes in the [H+] that occurs with changes
in PaCO2).1517 Hypercapnic hypoxemia creates the greatest
stimulus.1517
The sensitivity of the chemoreceptors and ventilatory
control centers to changes in arterial blood gases can be
determined by measuring the ventilatory responses to rises
in PaCO2 (hypercapnic ventilatory response [HCVR]) and
falls in PaO2 (hypoxic ventilatory response [HOVR]).9,10
These are measured by rebreathing methods. The end-tidal
partial pressure of carbon dioxide (PETCO2) and end-tidal
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 Chapter 10 Sleep and Respiratory Physiology 147

partial pressure of oxygen (PETO2) are determined on a system compliance is not an ideal method to test the neural
breath-by-breath basis (assumed to be alveolar values) and drive to breathe. The mouth occlusion pressure (P0.1)the
plotted against the ventilation at that time on a breath-by- mouth pressure measured 0.1 second after the start of inspi-
breath basis. A line is then drawn to fit the points. The HCVR ration (unexpected airway occlusion)can be used instead
is measured under hyperoxic conditions (minimizing the of ventilation as a better index of drive. Pressures at 0.1
effect of peripheral chemoreceptors) and the HOVR is mea- second are before voluntary changes in pressure can occur.
sured under eucapnic conditions (PaCO2 kept constant by Because there is no flow during occlusion, the P0.1 is not
removal of some of the CO2 from the system).16,17 The slope affected by airway resistance. However, maintaining ade-
of the HCVR is a measure of sensitivity to hypercapnia (Fig. quate ventilation with a high airway resistance may require
107A). However, the position of the curvethat is, set point a compensatory increase in ventilatory drive (increased
or base pointis also important. The slope of the HOVR (see P0.1). The P0.1 response to hypercapnia or hypoxemia is
Fig. 107B) is not constant and analysis is more complex. determined during rebreathing with intermittent airway
However, if expressed as ventilation versus the SaO2 (SpO2 occlusion (measurement of P0.1). The P0.1 values are plotted
is measured), the slope is linear (see Fig. 107C). versus PCO2, PO2, or SaO2 depending on the test.
If a person has a normal ventilatory control center but During sleep, the HCVR and HOVR are reduced during
abnormal lungs, high airway resistance, or abnormal tho- NREM compared with wake and decreased in REM sleep
racic cage, the slope of the ventilatory response to CO2 will compared with NREM sleep (Fig. 108).10,11 Figure 109
be lower (see Fig. 107A). Thus, measuring ventilation in a shows the breath-by-breath values of the ventilatory response
patient with a high airway resistance or low respiratory to PaCO2 in an obstructive sleep apnea (OSA) patient before
Minute ventilation (L/min)

Minute ventilation (L/min)

Minute ventilation (L/min)

Resistive
load

40 50 60 40 60 80 100 60 80 100
A PACO2 (mmHg) B PAO2 (mmHg) C SaO2 (mmHg)

FIGURE 107 Schematic representation of the hypercapnic ventilatory response (A) and the hypoxic ventilatory response (B and
C). If the hypercapnic response is performed with a resistive load, the slope is lower. This illustrates that this testing depends not
simply on the ventilatory control centers but also on the resistance and compliance of the respiratory center. PACO2 = alveolar partial
pressure of carbon dioxide (estimated from end-tidal values during the rebreathing test); PAO2 = alveolar partial pressure of oxygen
(estimated from end-tidal values during the rebreathing test); SAO2 = arterial oxygen saturation (actually SpO2 from oximetry).

20 P < .05
ke

15
ke
a

a
Aw

P < .05 4
Aw

3/
Ventilation (L/min)

Ventilation (L/min)

2 P < .05
4
3/
e
t ag e 2 P < .05
10 S ag 10
St
M REM
RE

5
0
30 40 50 100 90 80
A End-tidal PCO2 (mmHg) B Oxygen saturation (%)

FIGURE 108 A, The hypercapnic ventilatory response is reduced during nonrapid eye movement (NREM) sleep compared with
wake and decreased in rapid eye movement (REM) sleep compared with NREM sleep. PCO2 = partial pressure of carbon dioxide. B,
The hypoxic ventilatory response is also decreased during NREM compared with wake and REM compared with NREM. A and B, From
Douglas NJ, White DP, Weil JV, et al: Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 1982;126:286289.
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148 Chapter 10 Sleep and Respiratory Physiology

60 after CPAP treatment is that the patients on CPAP no longer

90 days developed an elevated nocturnal PaCO2 and, therefore, no
longer accumulated HCO3 at night to compensate (see next
section). A fall in the serum HCO3 would be associated with
Minute ventilation (L/min)

a leftward shift in the ventilatory response (see Fig. 1010).

ACID-BASE PHYSIOLOGY
40
Some basic information regarding acid-base physiology can
be useful in evaluating patients with sleep-related breathing
Control
disorders. The relationship of the pH (log [H+]) to the
serum HCO3 and PaCO2 is given by the logarithmic version
of the Henderson-Hasselbalch equation (Equation 1012). A
nonlogarithmic form of the Henderson-Hasselbalch equa-
20 tion relates the [H+] to the ratio of the PaCO2 and HCO3
55 65 75 (Equation 1013).21
Alveolar CO2 tension (mmHg)
pH = 6.10 + log ( HCO3 /0.03 PaCO2 ) pH = log[H + ]
FIGURE 109 The hypercapnic ventilatory response before and after continuous
Equation 1012
positive airway pressure (CPAP) treatment. The slope did not change but the curve
shifted to the left. Alveolar CO2 = estimated PACO2 from end-tidal sample of exhaled gas
PaCO2 [H ] in nanomoles/L = 10 moles/L
+ 9
during rebreathing test. From Berthon-Jones M, Sullivan CE: Time course of change in [H + ] = 24
ventilatory response to CO2 with long-term CPAP therapy for obstructive sleep apnea. Am [HCO3 ] HCO3 in mEq/L
Rev Respir Dis 1987;135:144147. Equation 1013
If a change in PaCO2 occurs, the body attempts to compen-
sate by changing the HCO3 in the same direction, thereby
Metabolic alkalosis minimizing the change in the PaCO2toHCO3 ratio (Fig.
Metabolic acidosis Normal
1011). However, compensation is never complete (pH
Slight Marked
Marked
Slight
remains below or above 7.4). Of note, at a pH of 7.40, the
A B C E [H+] is 40 nanomoles/L. In order to use the nonlogarithmic
D
form of the Henderson-Hasselbalch equation (Equation
30 1013), one can use the fact that around a pH of 7.40, when
Ventilation (L/min)

the pH increases (decreases) by 0.01 unit above or below 7.4,

20
10
35 45
PCO2 (mmHg)
FIGURE 1010 Changes in the hypercapnic ventilatory response with metabolic
acidosis and alkalosis. The slope did not change but the position of the curve shifted left
or right. PCO2 = partial pressure of carbon dioxide. From Oren A, Whipp BJ, Wasserman
K: Effects of chronic acid-base changes on the rebreathing hypercapnic ventilatory response
in man. Respiration 1991;58:181185.
(control) and after continuous positive airway pressure
(CPAP) treatment.18 The slope did not change but the set
point (baseline PaCO2) decreased and the position of the
curve shifted to the left. At any given PaCO2, the ventilation
is higher. A shift in curve position without a change in slope
can be seen with changes in HCO3 due to chronic metabolic
acidosis or alkalosis19,20 (Fig. 1010). One explanation for the
parallel shift in the hypercapnic ventilatory response curve
the [H+] decreases (increases) by approximately 1 nanomol/L
below or above 40 (Box 102). It is worth remembering that
a lower pH is associated with a higher [H+]. For example, a
pH of 7.35 corresponds to an [H+] of 45 and a pH of 7.45
corresponds to an [H+] of 35 nanomol/L. Box 102 presents
examples of acute and chronic respiratory acidosis.
In evaluating the acid-base status of an arterial blood gas,
55 a few simple rules are helpful. More comprehensive rules
exist but a useful rule is that for every 10 mm Hg the PaCO2
increases or decreases, the HCO3 increases or decreases
about 1 mEq/L acutely and 3 to 4 mEq/L chronically. If a
patients PaCO2 increased from 40 to 60 mm Hg after
chronic renal compensation, the HCO3 would be expected
to increase by 6 to 8 mEq/L. Similarly, the pH would be
expected to decrease by approximately 0.03 (Fig. 1011).
Assuming a baseline HCO3 of 24 mEq/L, this would result
in a HCO3 around 30 mEq/L. Noting electrolyte results can
be helpful when evaluating obese patients with severe sleep
apnea. If such a patient has chronic respiratory acidosis
(high PaCO2), he or she will usually have a high HCO3 (or
serum CO2). An elevated HCO3 in the absence of a reason
to have a metabolic alkalosis (e.g., diuretic) is a clue that
respiratory acidosis could be present. The utility of an ele-
vated HCO3 for identifying patients with the obesity
hypoventilation syndrome is discussed in Chapter 15.
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ACID BASE CHANGES FIGURE 1011 The major acid-base changes. For primary
respiratory changes, there is renal compensation, and for
Goal keep the PCO2 /HCO3 ratio unchanged
metabolic changes, there is respiratory compensation. PCO2 =
Primary Compensation partial pressure of carbon dioxide.

Respiratory acidosis Increased PCO2 Increased HCO3

Respiratory Decreased PCO2 Decreased HCO3

alkalosis
Metabolic acidosis Decreased HCO3 Decreased PCO2

Metabolic alkalosis Increased HCO3 Increased PCO2

General rule: for every 10 mmHg change in PCO2 the HCO3

changes by 3-4 chronically and 1 meq/L acutely

Or pH changes by .08 acutely or .03 chronically

BOX 102 ventilatory dysfunction (RVD).2225 Disorders with an OVD

Using the Henderson-Hasselbalch Equation pattern of impairment include asthma, chronic bronchitis,
(Approximate [H+] values corresponding to and emphysema. The term chronic obstructive pulmonary
different pH values near 7.40) disease (COPD) is used because patients typically have a
mixture of chronic bronchitis and emphysema in variable
[H+] (NANOMOLES/L) PH
proportions. Patients with asthma usually have a significant
30 7.50 component of reversible airflow obstruction. Patients with
35 7.45 COPD have a mixture of chronic bronchitis and emphysema
and may also have some improvement after inhaled bron-
40 7.40 chodilator. Chronic bronchitis is a clinical diagnosis based on
45 7.35 a history of sputum production, but the term is often used
50 7.30 for COPD patients with OVD who do not have a significant
component of emphysema. The RVD disorders are divided
Sample calculations: [H+] = 24 PaCO2/HCO3 into extrinsic RVD (involvement of the chest wall, pleura, or
24 ( 40 ) muscle weakness) and intrinsic RVD (lung parenchymal dis-
Normal 40 = pH = 7.40 Normal orders such as interstitial lung disease) (Box 103).
24
Spirometry, lung volume determination, and measure-
24 ( 50 ) ment of the diffusing capacity for carbon monoxide (DLCO)
Acute hypoventilation 48 = 7.32
25 are an essential part of the evaluation of all patients with lung
25 ( 50 ) disease or hypoventilation. Nomenclature of the lung
Chronic hypoventilation 44 = 7.36
27 volumes is illustrated in Figure 1012. The total lung capac-
PaCO2 = arterial partial pressure of carbon dioxide.
ity (TLC) is the lung volume at maximal inspiration, residual
volume (RV) is the lung volume at maximal expiration, and
the functional residual capacity (FRC) is the end-expiratory
lung volume. The RV is about 25% of TLC and FRC is
PULMONARY FUNCTION TESTING approximately 40% to 45% of TLC. The expiratory reserve
volume (ERV) and inspiratory capacity compose about one
Pulmonary function testing is often needed to evaluate third and two thirds of the vital capacity (VC). Recognition
patients with a low awake PaO2 (or SaO2) or to determine of either OVD or RVD can help guide further evaluation. In
the etiology of unexpected daytime hypoventilation or addition, if lung function abnormalities are documented, the
dyspnea on exertion. Sometimes pulmonary function severity as well as response to treatment can also be assessed.
testing is ordered after a sleep study reveals an unexplained Spirometry is a measurement of exhaled volume versus
low sleeping baseline SaO2 without discrete apneas or hypop- time (Fig. 1013). Spirometry cannot measure absolute
neas. Therefore, some knowledge of pulmonary function lung volumes (TLC, FRC, RV), but it is widely available.
testing can be very useful for the sleep clinician. Spirometry is also a convenient method to follow the course
The patterns of impairment in lung disease include of lung disease. The most important parameters include the
obstructive ventilatory dysfunction (OVD) and restrictive forced expiratory volume in 1 second (FEV1), the forced vital
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150 Chapter 10 Sleep and Respiratory Physiology

BOX 103 capacity (FVC), and the FEV1/FVC ratio. OVD is associated
Patterns of Pulmonary Function Abnormality with a reduced FEV1/FVC ratio, whereas the ratio is normal
or increased in RVD (see Table 105). OVD processes are
OVD associated with reductions in airflow, hence, a reduced FEV1.
A reduction in flow rates often with an increase in absolute In very mild disease, the FEV1 may be normal but the FEV1/
lung volumes (increase RV > TLC) FVC reduced. The RVD pattern of spirometry is character-
1. Asthma ized by a normal FEV1/FVC ratio and a reduced FVC.
2. Chronic bronchitis Bronchodilator testing is performed by administering
3. Emphysema inhaled bronchodilator to a patient who has not used a bron-
RVD chodilator before the study. American Thoracic Society cri-
teria21 for a significant bronchodilator response include an
A reduction in the total lung capacity with or without a
increase in the FEV1 or FVC by 12% AND an absolute increase
reduction in other lung volumes
of at least 200 mL. A large improvement of 15% to 40% is
1. Intrinsic RVDdue to parenchymal lung disease (e.g.,
interstitial lung disease) suggestive of asthma. However, asthmatics may not have an
2. Extrinsic RVDdue to chest wall, pleural disease, or acute bronchodilator response but may improve with chronic
muscle weakness bronchodilator therapy. Patients with COPD typically have
OVD = obstructive ventilatory dysfunction; RVD = restrictive ventilatory
no response (predominant emphysema) or a modest response
dysfunction. of 10% to 15% (predominant chronic bronchitis).

FIGURE 1012 A, Lung volume nomenclature. ERV = expiratory OVD Normal RVD
reserve volume; FRC = functional residual capacity; IC = inspiratory
capacity; RV = residual volume; TLC = total lung capacity; VC =
TLC
vital capacity; Vt = tidal volume. B, Changes in lung volumes with TLC
disease. In obstructive ventilatory dysfunction (OVD), the VC can be
decreased due to an increase in the RV that exceeds any increase VC
in the TLC. In restrictive ventilatory dysfunction (RVD), by definition,
there is a decrease in the TLC and the VC decreases due to a VC IC
VC
decrease in the total capacity that exceeds any decrease in the RV.
Vt
FRC
VC
ERV
RV
RV

0
A B

5 Lung volume here is RV SPIROMETRY EXAMPLES

Expiration
4
Normal
Volume (liters)

3
Mild OVD
Volume

2 FEV1 FVC Severe OVD

RVD

1
Inspiration Lung volume here is TLC
0
0 1 2 3 4 5 Time
Time (seconds)

FIGURE 1013 Left, Spirometry records exhaled volume versus time. Right, Typical patterns of obstructive ventilatory dysfunction (OVD) and
restrictive ventilatory dysfunction (RVD) are noted. OVD is characterized by a reduced forced expiratory volume in 1 secondtoforced vital capacity
(FEV1/FVC) ratio. Either OVD or RVD can result in a reduced vital capacitybut with different alternations in the total lung capacity (TLC) and residual
volume (RV) (see Fig. 1012).
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Lung volume testing by helium dilution or body plethys- pulmonary blood volume, and the Hb. CO diffuses across
mography is used to determine the FRC. The patient then the alveoli and binds to Hb. The diffusing capacity must be
performs a slow VC maneuver and the inspiratory capacity corrected for anemia if this is present. Destruction of the
(IC) and ERV are determined (see Fig. 1012A). Then the effective surface area for diffusion occurs with emphysema
TLC and RV are computed (TLC = FRC + IC and RV = FRC or parenchymal lung disorders causing RVD. Pulmonary
ERV). Note that the VC equals the difference between the vascular diseases that reduce the pulmonary blood volume
TLC and the RV. Changes in either the TLC, the RV, or both can reduce the diffusing capacity. Table 105 presents a
can decrease the VC. summary of pulmonary function findings and normal
By definition, RVD is associated with a reduced TLC. ranges. Of note, the pattern of near normal spirometry and
Ideally, a spirometric diagnosis of RVD should always be a decreased diffusing capacity can occur with emphysema,
confirmed by documenting a reduced TLC. In OVD, the interstitial lung disease, pulmonary vascular disease, or
TLC is normal or increased. The RV in OVD is usually anemia. Some patients with emphysema have minimal
increased (airtrapping) more than the TLC, and this can abnormalities in airflow but a reduced diffusing capacity.
result in a decrease in the VC. In RVD, the TLC is decreased Some patients with early manifestations of disorders of the
more than the RV, and this results in a decrease in the VC lung causing RVD can have a reduction in the diffusing
(see Fig. 1012B). capacity while the FVC and TLC are still normal.22 The situ-
The FRC is the resting end-expiratory volume and is the ation is especially common in lung disease due to medica-
volume at which the outward recoil of the chest wall is bal- tions (e.g., amiodarone, chemotherapy agents). In pulmonary
anced by the inward lung elastic recoil. The inspiratory activ-
ity (diaphragm, intercostals, sternocleidomastoid) is required
to reach TLC and expiratory muscle activity is required
(abdominal muscles) to reach RV. In OVD, the RV is the first TABLE 104
lung volume to be significantly affected (due to airtrapping). Clinical Use of the Diffusing Capacity
In advanced OVD, the RV is increased much more than the DIFFUSING
FRC and TLC. In severe OVD, the FRC and TLC can also DIFFUSING CAPACITY
be increased. CAPACITY NORMAL REDUCED
The DLCO is a noninvasive method to assess the ability
OVD Asthma Emphysema
of the lung to transfer gas (Table 104). As might be expected,
Chronic bronchitis COPD with
obstructive diseases that affect the alveoli (emphysema) are COPDpredominant emphysema
associated with a reduced DLCO. OVD due to asthma or chronic bronchitis
chronic bronchitis is usually associated with a relatively
normal DLCO. Disorders causing RVD that affect the lung RVD Extrinsic RVD Intrinsic RVD
parenchyma (alveolar filling or interstitial lung disease) are Normal or Anemia
associated with a reduced DLCO. Of note, early in these near- Emphysema
disorders, the DLCO may be reduced even though the FVC normal Interstitial lung
and TLC are still in the normal range. In extrinsic RVD spirometry disease
(respiratory muscle weakness or chest wall/pleural disor- Pulmonary
vascular disease
ders), the DLCO is relatively normal because the alveoli are
not directly affected by the disorder. The diffusing capacity COPD = chronic obstructive pulmonary disease; OVD = obstructive
ventilatory dysfunction; RVD = respiratory ventilatory dysfunction.
depends on the effective surface area for gas transfer, the

TABLE 105
Patterns of Pulmonary Function
NORMAL OVD INTRINSIC RVD EXTRINSIC RVD
FEV1 80120% of predicted Decreased Decreased Decreased
FVC 80120% of predicted Normal to decreased Decreased Decreased
FEV1/FVC >0.70 Decreased Normal Normal
TLC 80120% of predicted Normal to increased Decreased Decreased
DLCO 7580% of predicted Normalasthma, bronchitis Decreased Normal to mildly
(corrected for hemoglobin) Reducedsignificant emphysema decreased
Note: Mixed OVD + RVD = decreased FEV1/FVC ratio and reduced TLC.
DLCO = diffusing capacity for carbon monoxide; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; OVD = obstructive ventilatory dysfunction;
RVD = restrictive ventilatory dysfunction; TLC = total lung capacity.
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152 Chapter 10 Sleep and Respiratory Physiology

vascular disease (e.g., scleroderma), reduction in the diffus-
ing capacity can occur in association with minimal changes
in spirometry. A mixed pattern of OVD and RVD can occur
and is characterized by a reduced FEV1/FVC ratio in combi-
nation with a reduced TLC (normal or increased in OVD).
Severity criteria for OVD and RVD are somewhat arbi-
trary,2226 but some commonly used criteria are listed in
Appendix 101.
OBESITY
Because a significant percentage of patients with OSA have
obesity, it is useful to understand the typical pulmonary
function findings in this condition (Fig. 1014). In obesity,
the FRC is either reduced or reduced in relation to the
RV. Therefore, in simple obesity, the most common pulmo-
nary function finding is a reduced ERV. Usually, the TLC
and RV are normal, as is the VC. In contrast, the obesity
hypoventilation syndrome may be associated with reduc-
tions in the TLC and VC (see Fig. 1014). The finding of a
reduced TLC in a patient with severe obesity and OSA
could be a clue that the obesity hypoventilation syndrome
might be present.
Typically, muscle weakness affects both the inspiratory
muscles (diaphragm and intercostal muscles) and the expira-
tory muscles (abdominal muscles) at the same time. This
results in a pattern of low TLC, high RV, and low VC. Note
that at FRC, no muscle force is needed. One might predict
that patients with muscle weakness would have a normal
FRC. However, owing to chronic changes in the chest wall
and lungs in patients with chronic neuromuscular disorders,
the FRC is usually decreased. Most individuals with a normal
chest wall and lungs can reach TLC with pleural pressures of
20 to 30 cm H2O. If the chest wall and lungs are normal,
significant muscle weakness must occur before the lung
volumes and the VC change.
CHANGES WITH SIMPLE OBESITY AND THE OBESITY
HYPOVENTILATION SYNDROME (OHS)
Obesity
Simple hypoventilation
obesity syndrome
TLC

MUSCLE STRENGTH
Muscle Forces FRC

The muscle forces needed to reach different lung volumes RV

are illustrated in Figure 1015. The lung recoil is inward at
all lung volumes. The resting point of the chest wall is
approximately 65% to 70% of TLC (Fig. 1016). At lung
volumes above FRC but below the resting point of the chest
wall, chest wall recoil is outward (thereby assisting tidal
breathing). At TLC, the chest wall recoils inward and at
RV outward. Inspiratory muscle weakness causes a low
TLC. Expiratory muscle weakness causes an increased RV.
0
FIGURE 1014 Typical lung volume changes in simple obesity and in patients with
the obesity hypoventilation syndrome. In simple obesity, the most common finding is a
reduced expiratory reserve volume (ERV = FRC RV) due to a low-normal or low
functional residual capacity (FRC). In the obesity hypoventilation syndrome, the total
lung capacity (TLC) and vital capacity (VC) are decreased (VC = TLC RV). RV = residual
volume.

FIGURE 1015 Summary of the muscle forces needed at the different RESPIRATORY SYSTEM STATIC FORCES
lung volumes. At total lung capacity (TLC), inspiratory muscles are
needed to overcome inward lung elastic recoil and inward recoil of the
chest wall (CW). At residual volume (RV), expiratory muscles (along Lung
with lung recoil) are needed to balance the outward recoil of the chest Inspiratory
muscles
wall. At functional residual capacity (FRC), no muscle forces are needed. CW
TLC

At FRC
CW
Chest wall  Lung
FRC recoil recoil
Lung
RV
CW
0
Lung

Expiratory
muscles
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 Chapter 10 Sleep and Respiratory Physiology 153

100 Normal test of diaphragmatic weakness.30 In this posture, the chest

Resting
wall muscles are less effective and any weakness in the dia-
position
phragm is more evident.
80
% predicted TLC

60 CLINICAL REVIEW QUESTIONS

Kyphoscoliosis
severe obesity 1. What is the most commonly reduced lung volume in
40 obesity?
A. ERV.
B. FRC.
20
Recoil outward Recoil inward C. TLC.
D. RV.
20 10 0 10 20 2. Which of the following changes occur from wake to
Recoil pressure (cm H2O) sleep?
FIGURE 1016 The neutral point of the chest wall (resting position) is approximately A. Reduced VT, unchanged RR.
65% to 70% of total lung capacity (TLC). At higher volumes, the chest wall recoils B. Unchanged VT, increased RR.
inward, and at lower volumes, outward. Note that in kyphoscoliosis or moderate to
severe obesity, the resting point is shifted to lower lung volumes and the slope C. Unchanged minute ventilation, increased RR.
(compliance = volume/ pressure) is decreased. D. Reduced VT, increased RR.

3. Which of the following is associated with an increase in

PaCO2?
Maximum Inspiratory Pressure and A. Decreased alveolar ventilation.
Maximum Expiratory Pressure B. Decreased VD/VT ratio.
C. Decreased dead space.
Although the maximum inspiratory pressure (MIP) and
maximum expiratory pressure (MEP) are often said to be the D. Decreased CO2 production.
most sensitive tests of respiratory muscle strength, measure- 4. Which of the following would be most consistent
ment of these parameters requires patient cooperation and with a stable patient with muscle weakness and
special expertise.27 The apparatus to measure the MIP and hypoventilation?
MEP consists of a mouthpiece with a small orifice (typically
A. PaCO2 = 60, PaO2 = 55 mm Hg.
1 mm 15 mm) to provide a leak and an accurate pressure
transducer. The leak is required to prevent the patient from B. PaCO2 = 60, PaO2 = 70 mm Hg.
using cheek muscles to perform the maneuvers. The MIP is C. PaCO2 = 50, PaO2 = 50 mm Hg.
usually performed at RV, and the MEP is performed at TLC. D. PaCO2 = 50, PaO2 = 60 mm Hg.
Unfortunately, the published normal ranges are wide and
vary considerably between studies. In general, the pressures 5. A patient has weak expiratory muscle weakness but
decrease with age, they are higher in men than in women, fairly normal inspiratory muscle weakness. Which lung
and the MEP exceeds the MIP in normal individuals. For volume would be affected the most?
clinically significant changes in the FVC to begin to occur, A. TLC.
the MIP is usually less than 60 cm H2O. An MEP less than B. FRC.
60 cm H2O is associated with a reduced ability to cough and C. RV.
clear secretions. An American College of Chest Physicians
(ACCP) Consensus group recommended noninvasive 6. A patient has stable hypoventilation with a PaCO2 of
positive-pressure ventilation (NPPV) for progressive neuro- 70 mm Hg. What would the expected serum HCO3 be,
muscular disorders when the MIP was less than 60 cm H2O assuming a normal HCO3 value is 24 mEq/L?
(or FVC < 50% of predicted).28 One can be more confident A. 34.
of the finding of a reduced MIP when it is associated with a B. 28.
reduction in the VC. Studies of VC and MIP in patients with
C. 26.
neuromuscular disorders have found that reduction in VC
exceeds that predicted by loss of muscle strength.29 This is D. 40.
thought to be due to alterations in the mechanical properties
7. The relative hypercapnic ventilatory response is:
of the chest wall or lung. Thus, the VC is usually reduced
when clinically significant muscle weakness is present. Of A. Wake > NREM > REM.
special interest is the fact that performance of FVC testing B. Wake > REM > NREM.
in the supine position was also found to be a very sensitive C. Wake > NREM = REM.
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154 Chapter 10 Sleep and Respiratory Physiology

8. Chronic metabolic alkalosis is associated with which of 9. What column (A, B, or C) lists the correct expected PO2
the following phenomenon? values for the SaO2 values?
A. Increased PaCO2, shift in hypercapnic ventilatory A B C
response line to the right. SaO2 = 60% PO2 40 30 30
B. Decreased PaCO2, shift in hypercapnic ventilatory SaO2 = 75% PO2 60 40 40
response curve to the left.
SaO2 = 90% PO 2 75 60 80
C. Increased PaCO2, shift in hypercapnic ventilatory
response line to the left.
D. Decreased PaCO2, shift in hypercapnic ventilatory
response line to the right.

10. The following pulmonary function test results are most consistent with:
A. RVD intrinsic.
B. RVD extrinsic.
C. OVD-predominant asthmatic bronchitis.
D. OVD-predominant emphysema.

PREBRONCHODILATOR % PREDICTED POSTBRONCHODILATOR % CHANGE

FEV1 (L) 1.61 48 1.86 18
FVC (L) 3.32 75 3.93 18
FEV1/FVC 0.48
TLC 7.13 111
FRC 4.71 132
RV 3.72 188
DLCO 21.85 78
(For normal ranges, see Table 105.)

Answers 2. Seakins M, Gibbs WN, Milner PF, et al: Erythrocyte

1. A. FRC is reduced, but can be low normal in some
patients while the ERV is reduced.
2. A.
3. A.
4. B. (normal A-a gradient).
5. C.
6. A. The PaCO2 is increased by 30 mm Hg so the addi-
tional HCO3 would be 3 (3 to 4) or a 9 to 12 mEq/L
increase. The expected HCO3 would be around
3336 mEq/L.
7. A.
8. A. (see Fig. 1010).
9. B.
10. C. OVD, predominant asthmatic bronchitis. The FEV1/
FVC is decreased, there is a response to bronchodilator,
and the DLCO is at the lower limits of normal.
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 Appendix 10-1

Severity Criteria for Pulmonary Function Testing

OVD
FEV1 >60 to <80% predicted Mild
FEV1 4060% of predicted Moderate
FEV1 < 40% of predicted Severe

RVD
TLC or VC > 70% to <80% Mild
TLC or VC 6070% predicted Moderate
TLC or VC < 50% predicted Severe

DLCO
DLCO 6080% Mild
DLCO 40% to <60% Moderate
DLCO < 40% predicted Severe

Notes:
1. Severity criteria are arbitrary, the above are fairly simple to use.
2. Most severity scales for OVD use postbronchodilator FEV1.
3. The global initiative for lung disease (GOLD) criteria for COPD severity differ: < 0.70; mild, FEV1 > 80% of predicted; moderate, FEV1 5080% of
predicted; severe, FEV1 3050% of predicted; very severe, FEV1 < 30% of predicted or FEV1 < 50% of predicted and severe symptoms.
4. RVD severity criteria for intrinsic RVD usually are commonly based on the worst classification for the TLC and DLCO. A TLC moderate but DLCO
severe would be considered severe or FEV1 < 50% of predicted and severe symptoms.
COPD = chronic obstructive pulmonary disease; DLCO = diffusing capacity for carbon monoxide; FEV1 = forced expiratory volume in 1 second; OVD =
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obstructive ventilatory dysfunction; RVD = restrictive ventilatory dysfunction; TLC = total lung capacity; VC = vital capacity.

157
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Cardiac Monitoring during
Polysomnography
Chapter Points
Score sinus tachycardia during sleep for a sustained
heart rate > 90 bpm for adults.
Score sinus bradycardia during sleep for a sustained
heart rate < 40/min for ages 6 through adult.
Score asystole for cardiac pauses > 3 seconds for ages
6 through adult.
Score WCT for a rhythm lasting a minimum of 3
consecutive beats at a rate > 100/min with a QRS
duration 120 msec (0.12 sec).
Score NCT for a rhythm lasting a minimum of 3
consecutive beats at a rate > 100/min with a QRS
duration < 120 msec (0.12 sec).
Score Afib if there is an irregularly irregular ventricular
rhythm associated with replacement of consistent P
waves by rapid oscillations that vary in size, shape, and
timing.
When the heart rate is 150, consider aflutter with 2/1
block.
Change to 10-second window to better visualize ECG.
Sustained WCT (>30 sec) should be treated as an
emergency and it is likely ventricular tachycardia
(especially in patients with known coronary artery
disease). Emergency procedures in the sleep center
should be activated.
In lead II, the P wave should be upright.
It is essential that the technologist or ordering physician
document the presence of a pacemaker. It is also helpful
to know whether the patient has known Afib.
A sudden run of wider complex beats < 100 bpm (e.g.,
6070 bpm) is not WCT (by definition > 100 bpm).
Among other considerations, determine whether the
patient has a pacemaker. Pacemaker spikes may be
better visualized with a high filter of 100 Hz with the
60-Hz notch filter off.
The purpose of this chapter is to discuss the aspects of elec-
trocardiographic (ECG) monitoring relevant to polysom-
nography. For a detailed discussion of the ECG and related
disorders, the reader is referred to reference 1. The normal
ECG recording is composed of several different waveforms.
Chapter 11
Each waveform represents a different electrical event during
the contraction of the heart. The waveforms include the P
wave, QRS complex, and T wave (Fig. 111). The P wave
represents atrial depolarization (right atrium followed by
left). The QRS complex represents ventricular depolarization.
By convention, if the first deflection is negative, the deflec-
tion is called a Q wave. The first positive deflection is called
the R wave. The negative deflection following the R wave is
called the S wave. If a single negative deflection occurs, it is
termed the QS wave. The second positive deflection follow-
ing an S wave is called the R wave (Fig. 112). The entire
QRS duration should be less than 0.12 second. The T wave
represents ventricular repolarization. The U wave is a small
wave that follows the T wave. It may be absent or very small
and is usually in the same direction as the T wave but
approximately 10% of its amplitude.
The PR interval is the time from the start of the P wave
to the first part of the QRS complex (see Fig. 111). The PR
interval varies with heart rate (shorter with faster heart rate)
but is normally 0.12 to 0.2 second in duration. The time from
the start of the QRS until the end of the T wave is the QT
interval. The QT shortens with increases in heart rate. The
RR interval is the time between successive QRS complexes.
The heart rate in beats per minute (bpm) is 60/RR interval
(sec). The corrected QT duration (QTc) is based on heart rate
and is given by the formula
QTc = (QT interval ) / RR interval (sec )
Normal QTc < 0.44 sec
A prolonged QT (Fig. 113) can occur with congenital
long QT syndromes, medications including antibiotics
(erythromycin, clarithyromycin, levofloxacin), antipsychot-
ics (haloperidol, risperidone), tricyclic antidepressants,
antiarrhythmic medications (amiodarone, sotalol), and elec-
trolyte abnormalities (hypokalemia, hypomagnesemia). A
life-threatening complication of a long QT is the develop-
ment of polymorphic ventricular tachycardia (torsades de
pointes).
The ST interval is the time interval from the end of the
QRS complex (J point) to the start of the T wave. The ST is
usually isoelectric (zero potential as identified by the T-P
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160 Chapter 11 Cardiac Monitoring during Polysomnography

segment) but can be slightly up-sloping. The ST segment can
be changed by ischemia (ST depression), acute myocardial
infarction (ST elevation), or pericarditis (ST elevation).
The standard ECG uses 12 leads. In standard ECG record-
ing, electrodes are placed on the right and left arms (RA, LA)
and left leg (LL). A ground is placed on the right leg (RL).
Leads I, II, and III are then recorded as (I LA+/RA, II LL+/
RA, III LL+/LA) (Fig. 114). These leads plus an addi-
tional three frontal plane leads (aVF, aVR, aVL) are depicted
in Figure 115. In the standard ECG, transverse plane elec-
trodes are also recorded (precordial leads). The precordial
QRS
R
P wave T wave
leads V1 (fourth intercostal space to the right of the sternum),
V2 (fourth intercostal space to the left of the sternum), V4
(fifth intercostal space on the midclavicular line), V3 (mid-
point on a straight line between V2 and V4), V5 (lateral to V4
and on the anterior axillary line), and V6 (lateral to V5 on the
midaxillary line) are depicted in Figure 116. Each precor-
dial lead is recorded against linked left arm, left leg, and right
arm electrodes, with the right leg as ground.
ECG RECORDING DURING POLYSOMNOGRAPHY
In most sleep centers, a single ECG lead is recorded during
sleep monitoring. Monitoring of a single ECG lead is most
useful for determining the cardiac rhythm and the heart rate.
Determination of the QRS axis requires multiple frontal
plane electrodes. In addition, accurate determination of ST
changes requires both frontal and precordial electrodes. The
QRS duration in a single lead may not reflect the widest value
U wave if part of the QRS is isoelectric in that particular lead. Mul-
tiple precordial leads are also needed for differentiation of

R
ST R R
interval
R

S S

R R

PR
interval QRS
interval

QS Q S
QT interval Q

FIGURE 111 Nomenclature of components of the QRS complex. From Wagner GS FIGURE 112 Nomenclature of the QRS complex. Adapted from Wagner GS (ed):
(ed): Marriotts Practical Electrocardiography, 9th ed. Philadelphia: Williams & Wilkins, Marriotts Practical Electrocardiography, 9th ed. Philadelphia: Williams & Wilkins, 1994,
1994, pp. 1113. pp. 1113.

FIGURE 113 Long QT. The vertical gray lines are 1-second apart and the black bar marks the QT interval which is 0.55 second. The
RR interval is approximately 1 second, so that the QTc = 0.55 (prolonged). The patient was taking risperidone, which can prolong the
QT interval. The patient also appears to have ST elevation and a wide QRS. A 12 lead ECG is needed to assess the significance of these
findings. The patient was asymptomatic.
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 Chapter 11 Cardiac Monitoring during Polysomnography 161

  

 

 I


 III
  II

A B
FIGURE 114 A, The three leads I, II, and III. B, The three leads are moved so that they V1 V6
intersect at the heart. Lead II is in a heart basetoapex direction.
V5

V4
ECG FRONTAL PLANE LEADS
V2 V3
90
120 60

150 aVR aVL 30

FIGURE 116 Placement of the precordial leads V1 to V6. Adapted from Drew BJ, Califf
RM Funk M, et al: Practice standards for electrocardiographic monitoring in hospital
180 I 0 settings. Circulation 2004;110:27212746.

Lead II AASM Modified Lead II

150 30

III II
120 60
aVF 
90

I 

Eithoven triangle 
II
III 

FIGURE 115 Electrocardiogram (ECG) frontal plane leads.
the causes of wide-complex tachycardia (WCT). Some sleep
centers record three or more cardiac electrodes. The Ameri-
can Academy of Sleep Medicine (AASM) scoring manual2,3
recommends use of a modified lead II with the negative torso
electrode placed parallel with the right leg and below the
right shoulder and the positive electrode parallel to the left
leg (hip) on the lower left chest rib cage around the sixth to
seventh intercostal spaces (Fig. 117). The exact intercostal
level was not specified in the AASM scoring manual. Because
A B
FIGURE 117 A, Standard ECG lead II. B, Modified lead II recommended for sleep
recording by the American Academy of Sleep Medicine (AASM) scoring manual. From
Iber C, Ancoli-Isreal S, Chesson A, Quan SF for the American Academy of Sleep Medicine:
The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and
Technical Specifications, 1st ed. Westchester, IL: American Academy of Sleep Medicine,
2007, p. 39.
the main purpose is detecting the cardiac rhythm, a precise
location is not essential.
In the standard and modified lead II, the P wave, R wave,
and T wave are upright (Fig. 118). Examples of abnormal
P wave, ST elevation, and a peaked T wave are also shown
in this figure. A digital polysomnography (PSG) recording
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162 Chapter 11 Cardiac Monitoring during Polysomnography

FIGURE 118 Examples of waveforms. The normal P wave in lead

II is upright. An inverted P wave shows that this is not from the sinus
node. Examples of ST elevation and a peaked T wave are also noted.

Lead II

Abnormal P wave

ST elevation

Peaked T wave

1 sec

inspiration

ECG

Airflow

FIGURE 119 An example of sinus arrhythmia in a 5-year-old boy. The heart rate varies with the respiratory cycle. The heart rate increases with inspiration and
decreases with expiration. The average heart rate is approximately 100 bpm. The electrocardiogram (ECG) was recording during a period of low arterial oxygen
saturation.

viewed in a 10-second window corresponds to a traditional
ink pen recording at a paper speed of 30 mm/sec. The tradi-
tional ECG paper speed used for recording was 25 mm/sec.
Therefore, a 10-second PSG window provides a view similar
to a standard ECG and is useful to observe the details of the
ECG tracing. Most PSG software also has tools allowing
measurement of durations and intervals of interest. The
AASM scoring manual recommends that the ECG signal be
acquired with a sampling rate of 500/sec (a sampling rate of
200/sec is acceptable). The recommended low- and high-
frequency filter settings for display of the signal are 0.3 and
70 Hz, respectively.
A simple way to estimate heart rate is to count the number
of QRS complexes in 10 seconds and then multiply by 6 for
beats per minute. If the rhythm is irregular, a longer interval
of 20 to 30 seconds should be used for a more accurate esti-
mate of the average heart rate.
SINUS RHYTHM AND NORMATIVE DATA
FOR HEART RATE
Normal sinus rhythm is associated with an upright P wave,
R wave, and T wave in lead II. Each P wave is followed by a
QRS complex with a relatively constant PR interval. If there
is significant variability in heart rate with respiration, this is
often called a sinus arrhythmia (Fig. 119). In a sinus arrhyth-
mia, the heart rate increases with inspiration and decreases
during expiration. Traditionally, sinus bradycardia is defined
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 Chapter 11 Cardiac Monitoring during Polysomnography 163

as a heart rate less than 60 bpm and tachycardia greater than
100 bpm. However, the heart rate normally decreases during
sleep. The lowest heart rate in normal adults is usually during
nonrapid eye movement (NREM) sleep when there is an
increase in parasympathetic tone and a decrease in sympa-
thetic tone. A review of the evidence that formed the basis
for the AASM cardiac scoring rules by Caples and cowork-
ers2 reports unpublished data from the Sleep Heart Health
Study cohort of 2067 adult individuals. The individuals in
the analysis had an apnea-hypopnea index (AHI) lower than
5/hr and were not taking cardiac or antihypertensive medi-
cations. The 95% confidence interval based on mean 2
standard deviations (SD) for heart rate during sleep found a
minimum normative value of 43 bpm in men and 47.5 bpm
in women. The maximum normative values for heart rate
were 80.8 bpm for men and 84.7 bpm for women. Based on
this information, the new AASM cardiac scoring rules define
sinus bradycardia during sleep as a sustained heart rate
less than 40 bpm for adults and children 6 years and older
(Table 111). Here, sustained means longer than 30 seconds
in duration.4 It should be noted that normal individuals,
especially endurance-conditioned athletes, often exhibit
heart rates less than 40 bpm during sleep. The AASM cardiac
scoring rules also define sinus tachycardia during sleep in
adults as a sustained heart rate greater than 90 bpm (see
Table 111).
Defining normal heart rate limits is more complex in
children in whom the heart rate is faster than in adults. The
heart rate in normal children during wakefulness undergoes
a large decrease with age57 (Table 112). Scant information
TABLE 111
Cardiac Scoring Rules (AASM)
Score sinus tachycardia during sleep for a sustained heart
rate > 90 bpm for adults.
Score sinus bradycardia during sleep for a sustained heart
rate < 40/min for ages 6 through adult.
Score asystole for cardiac pauses greater than 3 seconds
for ages 6 years through adult.
Score wide-complex tachycardia for a rhythm lasting a
minimum of 3 consecutive beats at a rate > 100/min with
a QRS duration 120 msec (0.12 sec).
Score narrow-complex tachycardia for a rhythm lasting a
minimum of 3 consecutive beats at a rate > 100/min with
a QRS duration < 120 msec (0.12 sec).
Score atrial fibrillation if there is an irregularly irregular
ventricular rhythm associated with replacement of
consistent P waves by rapid oscillations that vary in size,
shape, and timing.
Note: The term sustained was defined in an FAQ from the AASM Scoring
Manual committee to be > 30 sec. Sustained wide-complex tachycardia and
sustained narrow-complex tachycardia are present for > 30 sec.
AASM = American Academy of Sleep Medicine; FAQ = frequently asked
question.
Adapted from Anonymous: Scoring Manual FAQs. Available at http://
www.aasmnet.org/Resources/PDF/FAQScoringManual.pdf
From Iber C, Chesson A, Ancoli-Israel S, et al: The Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specifications, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007.

TABLE 112
Normal Heart Rate during Wakefulness in Children
AGE MINIMUM MAXIMUM MEAN 2ND98TH PERCENTILE NO. OF SUBJECTS
<1 day 88 168 123 93154 189
12 days 57 170 123 91159 179
36 days 87 166 129 91166 181
13 wk 96 188 148 107182 119
12 mo 114 204 149 121179 112
35 mo 101 188 141 106186 109
611 mo 100 176 134 109169 138
12 yr 68 165 119 89151 191
34 yr 68 145 108 73137 210
57 yr 60 139 100 65133 226
811 yr 51 145 91 62130 233
1215 yr 51 133 85 60119 247
Adapted from Davignon A, Rautaharju P, Boiselle E, et al: Normal ECG standards for infants and children. Pediatr Cardiol 1979;1:133152.
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164 Chapter 11 Cardiac Monitoring during Polysomnography
is available for normative heart rates in children during sleep.
As in adults, one would expect a lower heart rate in sleep
than during wakefulness. The Cleveland Childrens Sleep and
Health Study6 (CCHS) in a group of children aged 8 to 11
years (AHI < 5/hr) reported the mean 2 SD heart rate
during sleep was 73 10 bpm overall, 70 9 bpm in boys,
and 75 9 bpm in girls. These values represented a 20%
reduction from waking values. A 95% lower confidence limit
of 51 bpm in boys and 57 bpm in girls was found. The cor-
responding upper limits for boys and girls were 89 bpm and
94 bpm, respectively. A recent study analyzed data from the
CCHS study and the Tucson Childrens Assessment of Sleep
Apnea (TUCASA) study.7 The study concluded that sleeping
heart rates in children are lower than wake and decrease
significantly with age. African American ethnicity, female
sex, and obesity were associated with faster heart rates. The
AASM scoring manual did not provide rules for scoring the
heart rate in children because of the age dependence and
scant data.
CONDUCTION SYSTEM
A brief review of the cardiac conduction system (Fig. 1110)
is useful for understanding the terminology of premature
beats and block. The electrical impulse during normal sinus
rhythm starts with an impulse from the sinoatrial (SA) node
located high in the right atrium near the entry of the superior
vena cava. The SA node is the major cardiac pacemaker
because the cells there have the highest intrinsic rate. The
impulse is conducted through atrial muscle without special
fibers until it reaches the atrioventricular (AV) node located
at the bottom of the right atrium near the interatrial septum.
The next part of the specialized conducting system is the
bundle of His (common bundle). The bundle splits into a
right bundle and a left bundle. The left bundle then splits into
Sinoatrial (SA) node
Atria
Atrioventricular (AV) node
His bundle (common bundle)
Left bundle
Left anterior
fascicle
Left posterior
fascicle
Right bundle
FIGURE 1110 The normal cardiac conduction system.
left anterior and right posterior fascicles. The Purkinje fibers
then transmit the signal to myocardial cells. Purkinje cells
have both pacemaking capability and the ability to rapidly
conduct electrical impulses. Impulses conducted via the
normal pathway produce a narrow QRS complex and coor-
dinated right and left ventricular contraction. Impulses orig-
inating in the AV node or His bundle (together termed the
AV junction) usually have a rate of 40 bpm and result in a
normal QRS duration. Impulses beginning below the separa-
tion of the common bundle result in wide QRS complexes.
Of note, if an impulse reaches the normal AV junction
during a relatively refractory period, it may be conducted
with a wide QRS (aberrant conduction). If an impulse arrives
at the AV junction very early during a refractory period, it
may not be conducted at all. This phenomenon does not
represent heart block but is simply a reflection that the AV
node does have a refractory period that depends on a number
of factors including the heart rate.
In summary, normally electrical impulses begin in the SA
node, traverse the AV node, and are transmitted out to the
ventricles by the Purkinje system via the left and right
bundles. When the P wave is not present or is not conducted,
slower pacemakers in the heart may function to continue
regular ventricular rhythm. Rhythms from pacemakers in
junctional areas (AV node and His bundle) usually have a
narrow QRS complex with a rate approximately 40 to 60 bpm
(junctional or nodal rhythm). If the rhythm originates from
a pacemaker in the ventricles, the QRS is wide and the rate
is slow (idioventricular rhythm). If the sinus node activity
slows sufficiently, one of the other pacemakers may cause
ventricular capture (so-called escape rhythms). The junc-
tional and idioventricular rates can increase above the typical
values in some circumstances. The terms accelerated junc-
tional rhythm and accelerated idioventricular rhythm (AVIR)
are used to describe these rhythms.
Bundle branch block (BBB) is due to dysfunction of either
the right or the left bundles (RBBB or LBBB) and results in
a wide QRS. The type of BBB is best identified using a 12-lead
ECG. RBBB and LBBB produce characteristic patterns in
leads I, V1, and V6. The pattern in lead II is variable. The
other cause of a widened QRS commonly encountered in
sleep centers is a ventricular pacemaker with the lead in the
right ventricle. This gives a pattern of an LBBB because the
right ventricle depolarized slightly before the left.
BRADYCARDIA AND AV BLOCK DURING SLEEP
The common causes of a slow heart rate during sleep are
listed in Table 113. A slow heart rate during sleep (sustained
heart rate < 40 bpm) can be a normal variant, associated with
the effects of medications, high parasympathetic tone, or
associated with disease of the conduction system (SA node,
AV node). Cyclic increases and decreases in heart rate are
commonly associated with untreated obstructive sleep apnea
(OSA). This phenomenon is often called tachycardia-
bradycardia cycles. However, in many patients, the lower
heart rate is typically greater than 40 bpm and the high heart
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 Chapter 11 Cardiac Monitoring during Polysomnography 165

TABLE 113 rate may not exceed 90 bpm. The heart rate typically acceler-
Causes of a Slow Heart Rate ates at apnea termination owing to withdrawal of vagal tone
and an increase in sympathetic activity. The slowing of the
Sinus bradycardia
heart rate at event onset is thought to be due to vagal tone.
Sinus pauses (>3 sec) Typically, the heart rate slows, then speeds up toward the end
Sinus node disorder (sick sinus syndrome) of the obstructive events with a sudden increase in heart rate
at apnea termination. Some PSG computer programs provide
AV block
a moving time average heart rate based on the ECG. Others
Medications simply record a heart rate output of the oximeter, which is a
Increased parasympathetic (vagal) tone moving time average (Fig. 1111).
AV = atrioventricular.
Sinus Pause/Asystole
The AASM scoring manual recommends scoring asystole if
a sinus pause is greater than 3 seconds in duration for ages
6 years through adult4 (Fig. 1112; see also Table 111). The

ECG

Heart Rate
85 85 83 81 80 80 80 80 80 80 79 76 72 71 71 71 69 67 66 66 71 81 88 94 96 95 93 91 88

Snore
Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen
SpO2 91 91 91 91 91 91 91 91 90 90 90 90 90 90 89 89 88 86 85 84 83 81 79 78 77 78 79 81 87

1 sec

FIGURE 1111 The heart rate during an obstructive apnea. The heart rate signal is the output of the oximeter (a moving time average) that tends to lag behind
the actual change in heart rate. Changes in the heart rate can be noted by changes in the RR interval, which widen at apnea onset then narrow at apnea termination.
ECG = electrocardiogram; SpO2 = pulse oximetry.

100 V
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E1-M2
Chin EMG
ECG

3.6 sec

FIGURE 1112 Three sinus pauses in a 30-second tracing. The second pause is longer than 3 seconds and should be reported as asystole according to the AASM Cardiac
Scoring Rules. ECG = electrocardiogram; EMG = electromyogram.
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166 Chapter 11 Cardiac Monitoring during Polysomnography

review paper providing evidence for scoring rules quotes
normative data in young healthy subjects2 that found sinus
pauses to be longer in males (range 1.202.06 sec) than in
females (1.081.92 sec). In trained athletes, up to 37% had
sinus pauses between 2 and 3 seconds. A study of a cohort
of 40- to 79-year-old individuals found the longest pause
during sleep to be 2 seconds.8 For this reason, sinus pauses
of 3 seconds or longer are scored as asystole.
Of note, a common cause of apparent sinus pause is a
nonconducted premature atrial impulse. This is discussed in
the section on Premature Beats (PBs).
AV Block
AV block is classified into three types1 based on ECG char-
acteristics that correlate with the location of the abnormality
in the conducting system or the influences of changes in
autonomic tone.
1. First-degree AV block is defined as a prolongation of PR
interval longer than 0.20 second (Fig. 1113). The normal
PR interval is usually 0.12 to 0.20 second. A prolonged
PR interval was found in between 0.5% and 2% of healthy
middle-aged males.
2. Second-degree AV block is defined when one or more
(but not all) of atrial impulses fail to reach the ventricle
because of abnormal conduction.
a. Mobitz type I (Wenckebach): A pattern of AV block in
which there are varying PR intervals. Usually, there is
progressive prolongation of the PR interval until a P
wave is not conducted (Fig. 1114). This is typical of
a block in the AV node, which is capable of variations
in conduction time. This type of second-degree AV
block is generally thought to be benign.
b. Mobitz type II: A pattern of AV block in which the PR
intervals are nearly constant (Fig. 1115). It is often
seen in the setting of BBB.
3. Third-degree AV block (complete AV block): None of
the atrial impulses are conducted to the ventricles
(Fig. 1116). One can often see both P waves and QRS
complexes, but they have no fixed relationship (AV
dissociation).

10 second
window
0.4 sec

30 second
window

FIGURE 1113 First-degree atrioventricular (AV) block. Top, A 10-second window shows a prolonged PR interval. Bottom, A 30-second window.
One can see the difficulty in noting the abnormality unless viewed in a 10-second window.

30 second
window

1 sec

10 second
window

A B C
1 sec

FIGURE 1114 Second-degree AV block type I (Wenckebach) viewed in 30-second and 10-second windows. Arrow shows nonconducted P wave. A, Note
that the PR interval at B is longer than at A. At C, P wave without a QRS.
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 Chapter 11 Cardiac Monitoring during Polysomnography 167

30 second
window

1 sec

10 second
window
0.3 sec

1 sec

FIGURE 1115 Second-degree AV block, Mobitz II. The PR interval is constant but some P waves (up arrows) are not conducted (no associated QRS).

1 sec

FIGURE 1116 Third-degree AV block. The down arrows show P waves with a PP interval that is fairly constant. The P waves have
no fixed relationship to the QRS (AV dissociation). Because the QRS is narrow, this means the pacemaker is in the AV junctionso-
called junctional rhythm. Here, the junction rate is slow at approximately 33 bpm.

The term AV dissociation means that the atrial and ven-

tricular rhythms have no relationship. This can occur with Aberrant conduction
third-degree block. However, other causes include an intrin- Long Short
sic ventricular rhythm that is faster than the sinus rhythm cycle cycle
(RR interval is shorter than PP interval).

Aberrant Conduction
When cardiac tissue responds to a stimulus, the reaction is
followed by a refractory period (dormant interval) during
which it cannot respond to a similar stimulus. The refractory
period of cardiac conducting paths is proportional to the
length of the preceding cycle (RR interval). Thus, a long
preceding cycle in combination with a short immediate cycle
predisposes to the cardiac conduction system being in a
refractory state. A wide QRS can occur even if the beat origi-
nates in a supraventricular location (SA node or AV junc-
tion). This occurs for three reasons1: (1) a refractory right or
left bundle fascicle, (2) anomalous supraventricular activa-
tion, or (3) a paradoxical critical rate.1 In the first case, the
impulse transverses the bundle of His but finds either the
right or the left bundle refractory. In the second case,
the impulse bypasses the AV node, arises in the AV node in
an eccentric location, or is abnormally conducted due to
diseased junctional fibers such that the impulse does not
FIGURE 1117 A schematic example of atrial fibrillation with irregular RR intervals
and normal QRS duration. The fifth beat has a wide QRS duration due to aberrant
conduction. The immediate cycle is short and the preceding cycle is long. These factors
predispose to aberrant conduction.
reach the left and right fascicles at the same time. In the third
case, a critical rate occurs above which part of the ventricular
conducting system is refractory. A preceding long RR inter-
val and a short current RR interval increases the chance of
aberrant conduction. Figure 1117 shows an example of a
beat with aberrant conduction when the preceding cycle is
long and the current cycle is short.
Premature Beats
PBs are QRS complexes not originating in the SA node that
occur earlier than the next expected sinus beat. These can
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168 Chapter 11 Cardiac Monitoring during Polysomnography

occur as a single PB, a pair of PBs (couplet of PBs), three PBs Ventricular premature beats (VPBs) invariably are associ-
(by convention, nonsinus tachycardia > 100 bpm). The PBs ated with a wide QRS (usually > 0.16 sec) and are not pre-
can also follow every normal beat (bigeminy), every second ceded by an abnormal P wave. There is usually a compensatory
sinus beat (trigeminy), or every third sinus beat (quadri- pause following the VPB with the next P wave occurring
geminy) (Table 114). about two PP intervals after the last normal P wave (Fig.
The characteristics of PBs are listed in Table 115. Supra- 1120). VPBs originate in a ventricular focus and can be
ventricular premature beats (SVPBs) are either atrial prema- conducted retrograde via the AV node to the atria. The ret-
ture beats (APBs), or junctional premature beats (JPBs). rograde P wave can be seen deforming the VPBs or following
Although exceptions occur, SVPBs usually have a narrow the beat. When all VPBs have the same morphology, they are
QRS complex and the QRS morphology resembles that of said to be unifocal (unimorphic or monomorphic). If VPBs
the normal sinus beats. In the case of APBs, there is usually originate from multiple ventricular areas, they are usually of
a visible abnormal P wave (sometimes called P) (Fig. 1118). different morphology (polymorphic VPBs).
The abnormal P wave may be negative in lead II or have a
different morphology than the sinus P waves. The APBs are
TACHYCARDIAS DURING SLEEP
also known as PACs (premature atrial complexes). The P
wave can be hidden in the preceding T wave. SVPBs usually The scoring criteria for narrow-complex tachycardia (NCT)
reset the SA node and the next sinus beat occurs less than and WCT are listed in Table 111. In both cases, there must
two PP intervals after the last normal P wave (Fig. 1119). If be 3 or more beats with rate greater than 100 bpm. Note
the SVPB is aberrantly conducted, the QRS can be wide. that this differs from sinus tachycardia during sleep, which
must have a sustained (>30 sec) rate of greater than
90 bpm. The common causes of tachycardias seen during
TABLE 114 sleep studies are shown in Table 116. Tachycardias are
Premature Beat Terminology divided into NCT and WCT. With a single ECG lead, it is
not possible to determine whether a WCT originates from a
1 beat A PB ventricular focus rather than a supraventricular focus with
2 beats A pair or couplet aberrant conduction. Therefore, the AASM scoring manual
3 beats Nonsustained rhythm
recommends scoring a WCT rather than a ventricular tachy-
(nonsustained tachycardia if cardia (VT). However, most WCTs are VT.
rate > 100 bpm)
>30 sec Sustained rhythm Narrow-Complex Tachycardia
PB follows every normal Bigeminy NCT is characterized by a QRS duration shorter than 0.12
sinus beat second, with 3 or more beats and a heart rate greater than
PB follows every second Trigeminy 100 bpm (Fig. 1121). The major types of narrow complex
normal beat tachycardias are listed in Table 116. The term paroxysmal
supraventricular tachycardia (PSVT) is used to describe a
PB follows every third Quadrigeminy
normal beat
diverse group of rhythms characterized by regular rhythm
and narrow QRS, when the morphology does not otherwise
PB = premature beat.
allow identification of atrial fibrillation (Afib) or atrial flutter.

TABLE 115
Characteristics of Premature Beats
SVPBS VPBS ALSO KNOWN AS PVCS
QRS complex Normal duration (usually), resembles sinus beats Wide QRS
Wide QRS can occur (aberrant conduction)
Source of rhythm Atria: APB Ventricles
Junctional (AV node + His)
Compensatory pause No (usually): SA node discharged (reset) Compensatory pause: sinus node not reset
P wave Atrial: P wave premature and abnormal Usually none
Junctional: none Retrograde P wave can occur
Exceptions APB: P wave can be obscured in preceding T wave May appear < 0.12 sec in a given lead if
part of wave is isoelectric in that lead
APB = atrial premature beat; AV = atrioventricular; PVCs = premature ventricular complexes; SA = sinoatrial; SVPB = supraventricular premature beat; VPBs =
ventricular premature beats.
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 Chapter 11 Cardiac Monitoring during Polysomnography 169

30 second
window

10 second
window

10 second
window

FIGURE 1118 Atrial premature beats (APBs) are shown with dark lines that are over the abnormal P wave. Note that the QRS intervals are normal in
duration and have the same morphology as the QRS in the sinus beats.

FIGURE 1119 Schematic representation of a premature

ventricular beat (PVB) with compensatory pause and an atrial
PP interval premature beat (APB) without pause.

2  PP interval

Sinus rhythm

2  PP interval Compensatory
pause

PVB with
compensatory
pause

No
2  PP interval Compensatory
pause

APB without
compensatory
pause
PP interval

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170 Chapter 11 Cardiac Monitoring during Polysomnography

30 second
window

Couplet

30 second
window
Quadrigeminy

2 pp intervals

10 second
window

FIGURE 1120 Tracings of PVBs illustrate a couplet, quadrigeminy, and the compensatory pause.

TABLE 116
Common Tachycardias during Sleep
The etiology of PSVT could be a rapidly firing ectopic focus
SINUS TACHYCARDIA DURING SLEEP in the atria or nodal area or via re-entrant mechanisms in
Rate > 90 sec for 30 sec. the AV nodal areas. AV re-entrant tachycardia is due to an
NARROW-COMPLEX TACHYCARDIA
accessory path outside the AV node (Wolff-Parkinson-
White), and AV nodal re-entrant tachycardia is due to a
3 consecutive beats, rate > 100 bpm, QRS duration
conduction loop through the nodal area. The reader is
< 0.12 sec
referred to reference 1 for further reading on this topic.
PSVT: usually regular, rate 120240 bpm PSVT has regular RR intervals, and Afib has irregular RR
Ectopic atrial tachycardia intervals. Atrial flutter can have regular or irregular RR inter-
Ectopic nodal tachycardia vals. Both Afib and atrial flutter, which are discussed later,
AV nodal re-entrant tachycardia, AV re-entrant can result in a ventricular rate greater than 100 bpm and
tachycardia
narrow QRS complexes. When a burst of NCT is short, it is
Afib: irregular atrial activity, ventricular activity irregular, often not possible to differentiate between PSVT and Afib.
rate variable
Aflutter: flutter waves 280300 bpm, ventricular response Afib and Atrial Flutter
is variable (2/1 block ventricular rate 150, 4/1 block
ventricular rate 70) Afib and atrial flutter can present as either NCT or WCT in
the sleep center. However, patients may also exhibit a ven-
MAT: irregular RR intervals, with three or more P wave
morphologies (atrial rate 100250 bpm) tricular rate less than 100 bpm due to the effects of medica-
tions on the AV node or intrinsic AV node disease. In the
WIDE-COMPLEX TACHYCARDIA case of Afib with an average ventricular response less than
3 beats, rate > 100 bpm, QRS duration > 0.12 sec 100 bpm, the rhythm is called Afib with a controlled ventricu-
Ventricular tachycardia: usually regular lar rate. If the average heart rate exceeds 100 bpm, the
rhythm is termed Afib with a rapid ventricular response (Afib
PSVT usually regular with RVR). The hallmark of Afib is that it is an irregular
SVT with aberrant conduction: usually regular rhythm (Fig. 1122). This occurs due to irregular conduction
Afib with aberrant conduction: regular, irregular via the AV node. In atrial flutter, the saw-toothshaped
flutter waves (called F waves) usually have a frequency of 250
Aflutter with aberrant conduction: often irregular to 300 bpm and are often discernible (Fig. 1123). The ven-
Afib = atrial fibrillation; Aflutter = atrial flutter; AV = atrioventricular; MAT = tricular rate can be regular (fixed AV block) or irregular
multifocal atrial tachycardia; PSVT = paroxysmal supraventricular tachycardia.
(variable AV conduction). An NCT of 150 bpm should
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 Chapter 11 Cardiac Monitoring during Polysomnography 171

100 V
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG

ECG

4 sec

FIGURE 1121 Narrow-complex tachycardia in a 30-second window. ECG = electrocardiogram; EMG = electromyogram.

30 second
window

10 second
window

FIGURE 1122 Atrial fibrillation. Absence of P waves and irregularly irregular RR intervals. The average rate is approximately 64 bpm. This is an example
of atrial fibrillation with a controlled ventricular response. Therefore, although abnormal, this would not qualify for narrow-complex tachycardia.

1 sec
30 second
window

0.85 sec
0.20 sec
10 second
window

FIGURE 1123 Atrial flutter. The saw-toothlike flutter waves are noted. They have a frequency of approximately 60/0.20 sec = 300/min. Note that owing
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to variable block, the ventricular response is variable. For the RR interval of 0.85 sec, the rate is 70 bpm (4/1 block).
172 Chapter 11 Cardiac Monitoring during Polysomnography
1 sec
FIGURE 1124 Nonsustained wide-complex tachycardia (WCT). The WCT is most likely ventricular tachycardia based on probability.
From a single ECG lead, differentiating supraventricular tachycardia with aberrant conduction (SVTAC) from ventricular tachycardia
(VT) is not possible.
always trigger the suspicion of atrial flutter with 2/1 block.
In this circumstance, the flutter waves may be hidden by the
preceding T wave. A sinus tachycardia with a heart rate of
150 bpm in the absence of an extreme situation such as
hypotension or exercise is unlikely. The ventricular response
to atrial flutter may also be approximately 70 bpm (4/1
block). Sometimes, the AV block can be variable resulting in
an atrial flutter with irregular RR intervals (see Fig. 1123).
Multifocal atrial tachycardia (MAT), also known as multi-
focal atrial rhythm if the rate is less than 100 bpm, is char-
acterized by at least three different P wave morphologies and
has an irregular PP and RR interval. MAT is often seen in
association with an exacerbation of chronic obstructive pul-
monary disease (therefore, it is uncommon in the sleep
center). Atrial fibrillation and MAT are the two rhythms
characteristically associated with irregular RR intervals.
Wide-Complex Tachycardia
WCT is characterized by a QRS of 0.12 sec or greater (Fig.
1124; see also Table 116). The two causes are VT (or
Vtach) originating in the ventricles or supraventricular
tachycardia with aberrant conduction (SVTAC) originating
from the atria or junctional areas. Even with multiple ECG
leads, differentiating VT from SVTAC is difficult. The lead
V1 has been used in emergency settings and intensive care
units to help distinguish VT from SVTAC. However, this is
beyond the scope of the sleep disorders center. At least three
wide complexes are the minimum to score WCT. Sustained
WCT is usually defined as longer than 30 seconds and non-
sustained WCT as less than 30 seconds. VT accounts for up
to 80% of cases of WCT in unselected populations. It accounts
for 95% of cases in patients with previous myocardial infarc-
tion. Sustained WCT in the sleep center should be consid-
ered VT until proved otherwise.
If sustained WCT occurs in the sleep center in an out-of-
hospital setting, the emergency medical services (EMS)
should be called (911) and emergency equipment including
an automated external defibrillator (AED) should be brought
to the bedside. If the patient is asleep, she or he should be
gently awakened and assessed for chest pain or shortness of
breath. If the sleep center is within the hospital, an emer-
gency code is usually called for rapid response.
For nonsustained ventricular tachycardia (NSVT), the
clinical setting and condition of the patient dictate the
actions. A symptomatic patient would require EMS activa-
tion (outpatient setting) or transfer to the emergency depart-
ment or evaluation of the patient by an in-house on-call
physician. An asymptomatic patient would usually require
notification of the primary physician or physician on call for
the sleep center. In order to be accredited by the AASM, a
sleep center must have clearly specified written procedures
for handling cardiac emergencies. In some sleep centers, it is
a policy to wake the patient up if recurrent NSVT is noted
to check for symptoms.9
Patients with NSVT require a cardiac evaluation if this
has not been recently performed. NSVT in patients with
structural heart disease has a poor prognosis without inter-
vention. A typical evaluation includes echocardiography
(evaluation for cardiomyopathy and valvular heart disease),
Holter monitoring, and stress testing to rule out coronary
artery disease.9
ADVERSE EVENTS DURING PSG
An investigation by Mehra and Strohl10 collected informa-
tion from 16,084 sleep studies and found that the incidence
of serious adverse events during nocturnal PSG was very low
at 0.35% and the incidence of death within 2 weeks of an
adverse event was 0.006%. A total of 56 events were noted.
These included 1 death due to VT in a patient with coronary
artery disease, 28 events noted during the study (due to
arrhythmias), and another 28 events noted after the study by
the scoring technologist (complex ventricular arrhythmias).
In the latter cases, the referring physician was notified of the
problem. Of the 28 nonfatal events noted during the sleep
study, only 1 patient reported chest pain and shortness of
breath.
PACEMAKERS AND WIDE-COMPLEX QRS
A detailed discussion of ECG patterns from BBBs and pace-
makers is beyond the scope of this chapter. However, an
example is presented here to emphasize a few points. The
sudden appearance of wide complexes on the ECG can cause
panic in the sleep center. Sometimes, the fact that the rate is
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 Chapter 11 Cardiac Monitoring during Polysomnography 173

FIGURE 1125 Atrial fibrillation with ventricular pacer activity. A 10-second window is shown. Although only the pacer spikes of
the last 3 wide beats are visualized, all the wide beats have the same morphology and are all paced beats. Note that the 3-beat run
of paced beats follows a long pause in ventricular activity (pacemaker activated when rate dipped below a cutoff). The dark upright
bars mark the pacer spikes. These were not well visualized until the 60-Hz filter was turned off and 100 Hz was used for the high filter.

FIGURE 1126 A dual-chamber pacemaker. On the left, the atrial pacer spikes are noted with a narrow QRS showing normal
conduction of the atrial impulse to the ventricles. The longer vertical black line marks an atrial pacer spike. On the right, both atrial
and ventricular pacer spikes are noted and the QRS is wide. The atrial impulse is not conducted normally and the ventricular pacer is
activated, leading to a wide QRS. The small vertical black lines mark pacer spikes.

less than 100 (often 60 or 70) is missed in the excitement.
However, in the prestudy evaluation, it is always helpful
if the sleep technologist asks the patient whether he or she
has a pacemaker. As mentioned previously, a ventricular
pacemaker with the pacing lead in the right ventricle will
produce wide-paced beats with an LBBB morphology. Pacer
spikes are often difficult to see. Using a high-frequency filter
of 100 Hz rather than the AASM-recommended high-
frequency filter setting of 70 Hz AND turning off the 60-Hz
filter may help in visualizing pacer spikes.
Figure 1125 shows a single-chamber ventricular pace-
maker in a patient in Afib with AV nodal dysfunction. When
the ventricular rate falls below a cutoff value, the ventricular
pacer fires producing a wide-complex QRS. Figure 1126
shows a tracing with a patient with a dual-chamber pacer
(one atrial and one ventricular lead). On the left portion of
the tracing, only the atrial pacer lead is activated. On the
right, both atrial and ventricular leads are pacing. This pro-
duces a wide QRS.
If all beats have a wide QRS and the patient does not have
a pacemaker, the patient likely has a BBB. From lead II alone,
one cannot accurately tell whether an LBBB or an RBBB is
present. In precordial lead V1 (see Fig. 116), an RBBB
usually is manifested by a QRS with an M or rSR pattern
(small initial upward deflection, downward deflection, larger
upward deflection). LBBB in V1 is usually manifested by a
QS or rS pattern. The QS pattern is a single wide down-
ward deflection (see Fig. 112). The rS pattern has a small
initial upward deflection followed by a wider downward
deflection. However, accurate diagnosis of a BBB requires a
12-lead ECG. One can simply comment in the sleep study
report that a wide QRS appeared to be present.
REFERENCES
1. Wagner GS (ed): Marriotts Practical Electrocardiography, 9th
ed. Philadelphia: Williams & Wilkins, 1994.
2. Caples SM, Rosen CLK, Shen WK, et al: The scoring of cardiac
events during sleep. J Clin Sleep Med 2007;3:147154.
3. Iber C, Ancoli-Isreal S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring
of Sleep and Associated Events: Rules, Terminology and Tech-
nical Specification, 1st ed. Westchester, IL: American Academy
of Sleep Medicine, 2007.
4. Anonymous: Scoring Manual FAQs. Available at http://
www.aasmnet.org/Resources/PDF/FAQScoringManual.pdf
5. Davignon A, Rautaharju P, Boiselle E, et al: Normal ECG
standards for infants and children. Pediatr Cardiol 1979;1:
133152.
6. Rosen CL, Quan SF, Xue W, et al: Pediatric heart rate data during
sleep from ethnically diverse cohorts. Sleep 2006;29:8889.
7. Archbold KH, Johnson NL, Goodwin JL, et al: Normative heart
rate parameters during sleep for children aged 6 to 11 years.
J Clin Sleep Med 2010;6:4750.
8. Bjerregaard P: Mean 24 hour heart rate and pauses in healthy
subjects 4079 years of age. Eur Heart J 1983;4:4451.
9. Gamaldo C, Sala RE, Collop NA: Complex arrhythmia during
a sleep studywhat to do? J Clin Sleep Med 2009;5:171173.
10. Mehra R, Strohl KP: Incidence of serious adverse events during
DaneshGroup.com
nocturnal polysomnography. Sleep 2004;27:13791383.
DaneshGroup.com

Monitoring of Limb Movements
and Other Movements
during Sleep
Chapter Points
A significant LM has a duration from 0.5 to 10 seconds
and a minimum amplitude 8 V above the baseline
resting EMG.
The minimum number of LMs to define a PLM series
(and, hence, LMs are PLMs) is four. The period length
between LMs in a PLM series is 5 to 90 seconds (onset
to onset).
If the onset of two LMs is separated by < 5 seconds,
they are counted as 1 LM.
LMs are not considered part of a PLM series if they
occur from 0.5 second before the start of a respiratory
event to 0.5 second after the respiratory event. That is,
LMs associated with respiratory events are not
counted.
PLMD is diagnosed when PLMS is present, RLS is not
present, and there is a clinical sleep disturbance or
complaint of daytime fatigue, and PLMS and the sleep
complaint are not better explained by another
disorder. PLMS is common and usually asymptomatic.
PLMD is uncommon.
ALMA and HFT occur at a faster rate than PLMs and
often occur at sleep-wake transitions. They are felt to
have no clinical significance.
The EMG changes associated with the RBD (REM sleep
without atonia) can occur in the chin EMG, chin EMG
and limb EMG, or limb EMG alone. The changes include
a sustained elevation of the chin EMG activity and TMA
in either the chin EMG, the limb EMG, or both.
The diagnosis of RBD requires BOTH finding REM
without atonia AND either PSG documentation OR a
history of dream-enacting behavior. In addition,
absence of REM-related epileptiform activity (rare) is
required to diagnose the RBD.
Bruxism can occur in any stage of sleep and wake and
a rhythmic pattern may be seen in the EEG or chin
EMG derivations. The diagnosis of bruxism requires at
least two episodes of audible sound of teeth
Chapter 12
grindingdiagnosis not based on EEG/EMG findings
alone. If no sounds are audible, one might simply
comment that a pattern typical of bruxism was
observed.
The frequency of rhythmic movement disorder
movements is 0.5 to 2 Hz. The amplitude of
movements must be at least twice the background.
Video PSG is extremely helpful in making the diagnosis
and documenting the type (e.g., head banging, body
rocking).
A number of movement disorders are classified in the
International Classification of Sleep Disorders, 2nd edition
(ICSD-2), as sleep-related movement disorders1 (Table 121).
The restless legs syndrome (RLS) and periodic limb move-
ment disorder (PLMD) are discussed in detail in Chapter 23.
This chapter discusses monitoring of limb movements (LMs)
and also the scoring rules for periodic limb movements in
sleep (PLMS), bruxism, the rhythmic movement disorder
(RMD), and the rapid eye movement (REM) sleep behavior
disorder (RBD). The chapter also covers three LM patterns
considered to be benign conditions: alternating leg move-
ment activity (ALMA), hypnagogic foot tremor (HFT), and
excessive fragmentary myoclonus (EFM). These three LM
patterns are listed in the ICSD-2 under Isolated Symptoms
and Apparently Normal Variants.
LIMB MONITORING TECHNIQUES
Recording of limb muscle electromyogram (EMG) activity
in polysomnography (PSG) is used to document the pres-
ence and frequency of LMs.2,3 The EMG activities of the right
anterior tibialis (RAT) and left anterior tibialis (LAT) muscles
are routinely monitored. However, in patients with suspected
RBD, arm muscle EMG activity is also recorded because this
disorder is associated with abnormal EMG activity during
REM sleep in the arms and legs as well as the chin deriva-
tions. The classic periodic leg movement (PLM) consists of
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176 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep
TABLE 121
Sleep-Related Movement Disorders (ICSD-2)
Restless legs syndrome
Periodic limb movement disorder
Sleep-related leg cramps
Sleep-related bruxism
Sleep-related rhythmic movement disorder
Sleep-related movement disorder, unspecified
Sleep-related movement disorder due to drug or
substance
Sleep-related movement disorder due to medical
condition
ICSD-2 = International Classification of Sleep Disorders, 2nd ed.
Data from American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
extension of the big toe, dorsiflexion at the ankle, and some-
times flexion at the knee and hipsimilar to the movement
associated with the Babinski reflex. The PSG finding of PLMs
is a very common finding and usually not associated with
symptoms. However, PLMs can result in sleep disturbance
of the patient or bed partner.
Leg EMG is recorded using bipolar AC amplifiers with
surface electrodes using methods similar to those used to
record chin EMG activity. The electrodes should have an
impedance less than 10 K (<5 K is preferred). The rec-
ommended low- and high-frequency filter display settings
are 10 Hz and 100 Hz, respectively. Use of a 60-Hz notch
filter is discouraged. Having the patient move the left and
right legs (wiggle toes) is part of the biocalibration series. In
electroencephalogram (EEG) derivations that use a 35-Hz
high-frequency filter, turning off the 60-Hz filter has rela-
tively little effect. However, given the 100-Hz high-frequency
filter setting used for leg EMG recording, turning off the
60-Hz filter will significantly increase signal amplitude if
60-Hz contamination is present. This can be minimized by
low electrode impedance.2,3
Separate EMG electrodes are placed along the long axis
of the belly of the anterior tibialis muscle around the middle
of the muscle (Fig. 121). The American Academy of Sleep
Medicine (AASM) scoring manual3 recommends that the
electrodes be placed either 2 to 3 cm apart or one third the
length of the anterior tibialis muscle, whichever is shorter.
As discussed later, because voltage amplitude criteria are
used to identify significant LMs, the relaxed leg EMG activity
should be less than 5 V. Both legs should be monitored
for the presence of LMs. Using a separate channel (tracing)
for each leg is strongly preferred. Combining electrodes from
the two legs to give a single recorded channel may suffice for
some clinical settings, though it should be recognized that
this strategy may reduce the number of detected LMs. Move-
ments of the upper limbs may be sampled if clinically
Stress
loop Extensor
RAT1 digitorum
LAT1
RAT2 LAT2
A B
FIGURE 121 A, Placement of electrodes for monitoring right (RAT) and left anterior
tibialis (LAT) electromyogram (EMG) activity (RAT, LAT). B, Placement of electrodes for
monitoring the activity of forearm muscles (extensor digitorum).
indicated. The extensor digitorum is commonly monitored.
The muscle is on the lateral/dorsal aspect of the forearm and
is an extensor of the digits (see Fig. 121). Placement of the
electrodes to monitor the extensor digitorum is along the
long axis of the belly of the muscle separated by a few cen-
timeters. The location of the muscle can be determined by
having the patient extend the arm with the palm down and
then make a fist (opening and closing the hand). During
biocalibration, the patient is asked to extend the digits to
check for signal adequacy.
CRITERIA FOR LMS AND PLMS
In the following discussion, individual leg (limb) move-
ments are denoted by LM, individual periodic leg move-
ments as PLMs, and the PSG finding of periodic limb
movements in sleep by PLMS. Although leg movements
(RAT, LAT EMG) are typically monitored, the term periodic
limb movements is used to be more inclusive. Scoring crite-
ria for PLMs proposed by Coleman2 were widely used and
included in the International Classification of Sleep Disor-
ders, 1st edition4 (ICSD-1). Subsequently, a task force of the
American Sleep Disorders Association published recom-
mendations for recording and scoring LMs5 using similar
scoring criteria and providing many illustrative tracings of
LMs. The ICSD-2 used these criteria for defining PLMs.4
Significant LMs were 0.5 to 5 seconds in duration with an
amplitude at least one quarter of the LM amplitude during
biocalibration.1 Subsequently, the scoring criteria were
revised by the World Association of Sleep Medicine
(WASM) in collaboration with the International Restless
Legs Syndrome Study Group (IRLSSG).6 The major change
was extending the maximum duration of LMs to 10 seconds
and using voltage amplitude criteria. These criteria for
scoring LMs and PLMs are identical with the recommenda-
tions of the recently published AASM scoring manual.3,7 Of
note, the resting anterior tibialis EMG activity should be
less than 5 V.
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 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep 177

The current criteria for determining a significant LM
event are listed in Table 122. In the new criteria, a signifi-
cant LM has a duration from 0.5 to 10 seconds with a
minimum amplitude 8 V above the resting leg EMG. The
time of onset is the time at which the amplitude increased to
8 V above baseline resting activity, and the end of the LM
(offset) is defined as the START of a period lasting at least
0.5 second during which the EMG does not exceed 2 V
above resting EMG (Fig. 122). Use of voltage criteria based
on an absolute increase in microvolts above the resting base-
line requires a stable resting EMG for the relaxed anterior
tibialis muscle. The absolute signal should be no greater than
10 V between negative and positive deflections (5 V).
The AASM scoring manual also provides rules for defin-
ing a PLM series (Table 123), that is, criteria for identifying
a LM as a PLM. The minimum number of consecutive LMs
TABLE 122
Rules Defining a Significant Leg Movement Event
1. Minimum duration of an LM event is 0.5 sec.
to define a PLM series is 4 consecutive LMs. The time from
onset of one LM to the onset of the next LM is 5 to 90
seconds. LMs on different legs separated by less than 5
seconds between LM onsets are counted as a single LM.
Figure 123 presents a 90-second segment of left and right
anterior tibial EMG tracings.
LMs ASSOCIATED WITH RESPIRATORY
EVENTS ARE NOT SCORED
An LM should not be scored if it occurs during a period
from 0.5 second before an apnea or hypopnea to 0.5 second
after an apnea or hypopnea (LMs associated with respira-
tory events are not scored).3 The scoring rules did not provide
information about scoring LMs associated with respiratory
TABLE 123
Rules Defining a Periodic Leg Movement Series*
1. The minimum number of consecutive LM events to
define a PLM series is 4 LMs.

2. Maximum duration of an LM event is 10 sec.
3. The minimum amplitude of an LM event is an 8-V
increase in EMG voltage above resting EMG.
4. The timing of the onset of an LM event is defined as the
point at which there is an 8-V increase in EMG above
resting EMG.
5. The timing of the ending of an LM event is defined as
the START of a period lasting at least 0.5 sec during
which the EMG does not exceed 2 V above resting EMG.
EMG = electromyogram; LM = leg movement.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
Events: Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
American Academy of Sleep Medicine, 2007, pp. 4142.
2. The minimum period length between LMs (defined as
the time between onsets of consecutive LMs) to include
them as part of a PLM series is 5 sec.
3. The maximum period length between LMs (defined as
the time between onsets of consecutive LMs) to include
them as part of a PLM series is 90 sec.
4. LMs on two different legs separated by < 5 sec between
movement onsets are counted as a single LM.
*Criteria for LMs to be considered PLMs.
Note: It is understood that PLMS means that the LMs occur during sleep.
LM = leg movement; PLM = periodic leg movement.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
Events: Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
American Academy of Sleep Medicine, 2007, pp. 4142.

Inter-LM interval

LM duration

Onset threshold Onset Offset

8 V above
baseline

Offset threshold
2 V above
resting baseline

0 V
Resting baseline
(should be 5 V)

FIGURE 122 Criteria for onset and offset of leg movements (LMs). The time of onset is the time at which the amplitude increased to
8 V above the baseline resting activity. The end of the LM (offset) is defined as the START of a period lasting at least 0.5 second during
which the EMG does not exceed 2 V above the resting EMG. Adapted from Zucconi M, Ferri R, Allen R, et al: The official World Association
of Sleep Medicine (WASM) Standards for Recording and Scoring Periodic Leg Movements in Sleep (PLMS) and Wakefulness (PLMW) developed
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in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med 2006;7:175183.
178 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep

1 sec

7.8 sec

LAT  10 V

RAT  50 V

A B C D

FIGURE 123 A 90-second tracing of the left anterior tibilais (LAT) and right anterior tibialis (RAT) EMGs. The broken lines in the LAT
tracing are +10 V amplitude lines. The dark bars are durations in seconds. According to the scoring rules, a total of 5 periodic limb
movements (PLMs) are shown. In group A, there is 1 PLM. In group B, there is 1 PLM. In group C, there is 1 PLM because limb
movements (LMs) whose onset is separated by less than 5 seconds are considered as 1 LM. In group D, there are 2 PLMs.

Nasal pressure
NO therm
Chest
Abdomen

SpO2
LAT
RAT
90 seconds

FIGURE 124 The LMs are not counted as part of a PLM series because they occur in association with respiratory events. LAT = left anterior tibialis; NO = nasal-oral
thermal flow; RAT = right anterior tibialis; SpO2 = pulse oximetry.

effortrelated arousals (RERAs). However, some clinicians
would extend the previous rule to RERAs. It is not uncom-
mon for LMs to be noted at apnea termination even if an
associated cortical arousal is not present. In Figure 124, the
leg EMG bursts associated with respiratory events are not
scored as LMs or PLMs.
ASSOCIATION OF AROUSALS WITH PLM
According to the AASM scoring manual, an arousal and
PLM should be considered associated with each other (Fig.
125) when there is less than 0.5 second between the END
of one event and the ONSET of the other event, regardless
of which is first. This recommendation differs from previous
criteria, which required the arousal to follow the onset of the
PLM by not more than 3 seconds.
PERIODIC LIMB MOVEMENTS IN SLEEP
Of note, the term PLMS implies that PLMs occur during
sleep. The AASM scoring manual3 recommends reporting
the number of PLMS and the periodic limb movement in
sleep index (PLMSI), which is the number of PLMs per hour
of sleep. The number of PLMs associated with arousal and
the periodic limb movement in sleep arousal index (PLMSAI)
should also be reported.
PLMSI = 60 number of PLMs/TST (min )
PLMSAI = 60 number of PLMs with arousal/TST (min )
PERIODIC LIMB MOVEMENTS IN WAKE
The AASM scoring manual did not recommend criteria for
scoring periodic limb movements during wake (PLMW). The
WASM in collaboration with the IRLSSG6 published recom-
mendations for PLMW. The criteria for PLMW events is the
same as for PLMS events except that the patient is awake (Fig.
126). The PLMW index is defined as the number of PLMW
events divided by wake time (hr) from lights out to lights on
while the patient is in bed. That is, time when the patient is
out of bed or sitting on the side of the bed is not included. Of
note, frequent PLMW events are highly suggestive of the RLS.
If PLMW events are noted, the patient history should be
reviewed to determine if RLS symptoms are reported.
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 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep 179

100 V
F4-M1
1 sec C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
CFLOW
Chest

Abdomen
LAT
RAT
SpO2
94 94 93 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 94 95 95 94 94 94 94 94 94 94 94

FIGURE 125 A LM (part of a PLM series) is associated with an arousal. Note that the LM on the LAT tracing and the LM on the RAT tracing are counted as a single
LM. CFLOW = positive airway pressure device flow signal; ECG = electrocardiogram; LAT = left anterior tibialis; RAT = right anterior tibialis; SpO2 = pulse oximetry.

50 V
1 sec F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
Flow
Chest

Abdomen

RAT
LAT
SpO2
96 96 96 96 96 96 95

FIGURE 126 PLMs in wake. A 60-second tracing with the patient in stage W during the start of a continuous positive airway pressure (CPAP) titration. Flow = machine
flow (CFLOW). PLMs in wake are noted. The patient reported severe symptoms of the restless legs syndrome. ECG = electrocardiogram; EMG = electromyogram; LAT =
left anterior tibialis; RAT = right anterior tibialis; SpO2 = pulse oximetry.

SUGGESTED IMMOBILIZATION TEST

The Suggested Immobilization Test (SIT) was developed to
help make the diagnosis of the RLS.8 The test detects and
counts PLMW. The patient sits with the legs outstretched and
attempts to keep the legs still for 30 minutes to an hour. EMG
recording of the left and right anterior tibialis muscles is
performed. The test is often administered in the evening. The
combination of rest and monitoring in the evening worsens
RLS. In one study of the SIT, patients with RLS had signifi-
cantly more PLMW than controls (76.1/hr vs. 26.9/hr). In
this study, using a PLMW index of 40/hr to diagnose RLS,
the sensitivity and specificity were 81% and 81%, respectively
(compared with RLS clinical criteria based on history).
CLINICAL SIGNIFICANCE OF PLMS
PLMS is discussed in more detail in Chapter 23. There are
no widely accepted criteria for what constitutes a normal,
mildly, moderately, or severely increased PLMSI. In the
ICSD-1,4 the following severity scheme was recommended:
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180 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep

PLMSI less than 5/hr normal, 5 to 25 mild, 25 to less than
50/hr moderate, and greater than 50/hr severe. A PLMSAI
greater than 25/hr was identified as severe. It has been rec-
ognized that most patients with PLMS in the absence of the
RLS are usually asymptomatic. Approximately 80% to 90%
of patients with RLS will have PLMs on a given sleep study.9
The PLMD (clinical sleep disturbance or daytime fatigue due
to PLMS without RLS) is thought to be rare. The new AASM
scoring manual does not provide a scheme for grading sever-
ity of the PLM index. The ICSD-2 requires a PLM index of
15/hr in adults and 5/hr in children as criteria for the diag-
nosis of the PLMD (Table 124).1
OTHER LMS DURING SLEEP
In the following sections, other identifiable LM patterns are
discussed, including ALMA, HFT, and EFM. To date, the
presence of these patterns does not appear to be associated
with clinically significant disorder. However, ALMA and
HFT are fairly common and are sometimes confused with
PLMs.
Of note, PLMS during REM sleep (stage R) is uncommon
except in patients with the RBD. PLMs should not be con-
fused with transient muscle activity in the leg EMG that can
occur during stage R. Transient muscle activity is discussed
in a later section.
ALTERNATING LEG MUSCLE ACTIVATION
ALMA7,1012 is characterized by EMG bursts that alternate
between the legs (Fig. 127). Because there have been no
reported clinical consequences of this pattern, it is believed
TABLE 124
Periodic Leg Movement Disorder Diagnostic
Criteria (ICSD-2)*
A. PLMs presentLMs meet criteria to be PLMs
i. 0.510 sec in duration.
ii. Amplitude > 8 V above baseline.
iii. In a sequence of four or more movements.
iv. Onsets of consecutive LMs 5 and 90 sec.
B. PLM index > 15/hr adults and > 5/hr in children (in most
cases).
C. There is a clinical sleep disturbance or complaint of
daytime fatigue.
D. The PLMs and clinical sleep disturbance are not better
explained by another current sleep disorder or medical,
neurologic, or psychiatric disorder.
Notes:
1. A diagnosis of RLS excludes PLMD.
2. If PLMs are present without a sleep complaint, they can simply be noted
as a PSG finding.
3. If only the bed partners sleep is disturbed, this is not sufficient to make a
diagnosis of PLMD.
*Updated according to the AASM scoring manual.
AASM = American Academy of Sleep Medicine; LMs = leg movements;
PLMD = periodic leg movement disorder; PLMs = periodic leg movements;
PSG = polysomnography; RLS = restless leg syndrome.
Data from American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005; and Iber C,
Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep
Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
American Academy of Sleep Medicine, 2007, pp. 4142.

F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Nasal pressure

No airflow
Chest
Abdomen

SpO2
96 96 96 96 96 96 96 96 96 96 96 96 96 96 96 97 97 97 97 97 97 97 97 97 97 97 97 97 97
LAT

RAT
100 V

FIGURE 127 Alternating leg movement activity (ALMA). A 30-second tracing shows EMG bursts alternating between the legs. ECG = electrocardiogram; LAT =
left anterior tibialis; RAT = right anterior tibialis; SpO2 = pulse oximetry.
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 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep 181

to be a benign finding. ALMA can often occur in association TABLE 125

with arousals or at sleep-wake transitions.
The usual range of duration of ALMA EMG bursts is 100
to 500 msec (see Fig. 127). The AASM scoring manual cri-
teria for ALMA are listed in Table 125. ALMA consists of
short EMG bursts that alternate between the legs and are
higher in frequency than PLMs. The minimum frequency of
ALMAs is 0.5 Hz, meaning that the onsets can be separated
by no more than 2 seconds (in contrast, individual PLMs are
separated by a minimum of 5 sec).
HYPNAGOGIC FOOT TREMOR
7,11,13
HFT is a phenomenon characterized by a pattern of leg
EMG bursts that is more rapid than those seen with PLMs.
The usual range for the duration of HFT bursts is 250 to
1000 msec. The pattern may be seen during wakefulness
or associated with arousal from sleep (Fig. 128). Unlike
ALMA, the EMG bursts of HFT do not alternate between
the legs. The maximum time period between onset of HFT
EMG bursts is 3.3 seconds. The AASM scoring manual cri-
teria for HFT are listed in Table 126.
A summary of criteria for scoring PLMs, ALMAs, and
HFTs is shown in Table 127 for comparison.
Scoring Criteria for Alternating Leg
Movement Activity
These rules define ALMA:
1. Four ALMAs is the minimum number of discrete and
alternating bursts of leg muscle activity needed to score
an ALMA series.
2. The minimum frequency of alternating EMG bursts in
ALMA is 0.5 Hz (2 sec duration between bursts).
3. The maximum frequency of alternating EMG bursts in
ALMA is 3.0 Hz (0.33 sec duration between bursts).
ALMA = alternating leg movement activity; EMG = electromyogram.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
Events: Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
American Academy of Sleep Medicine, 2007, pp. 4142.
TABLE 126
Scoring Criteria for Hypnagogic Foot Tremor
These rules define HFT:
1. The minimum number of bursts needed to mask a train
of bursts in HFT is 4.
2. The minimum frequency of the EMG bursts of HFT is
0.3 Hz (3.3 sec between onset of bursts).

EXCESSIVE FRAGMENTARY MYOCLONUS
EFM7,11,13,14 (Fig. 129) is defined by a characteristic EMG
pattern in the leg tracings consisting of very brief EMG
bursts (<150 msec). It is thought to be a benign phenome-
non. It most cases, no movements are visible, or if present,
they are much like the small twitchlike movements of the
3. The maximum frequency of the EMG bursts of HFT is
4 Hz (0.25 sec between onset of bursts).
EMG = electromyogram; HFT = hypnagogic foot tremor.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
Events: Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
American Academy of Sleep Medicine, 2007, pp. 4142.

F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
ECG

Nasal pressure
No therm
Chest

Abdomen

SpO2 98 98 98 98 98 98 98 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97 97

LAT
RAT
100 V
100 uv

FIGURE 128 A 30-second tracing of hypnagogic foot tremor (HFT) during stage W. ECG = electrocardiogram; LAT = left anterior tibialis; RAT = right anterior
tibialis; SpO2 = pulse oximetry.
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182 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep

TABLE 127
Comparison of Periodic Leg Movements, Alternate Leg Movement Activity, and Hypnagogic Foot
Tremor Events
LMS, PLMS ALMA HFT
EMG burst duration 0.510 sec 100500 msec 2501000 msec
Number of bursts in a series 4 4 4
Minimum frequency (1/sec) 0.01 0.5 0.3
Maximum frequency (1/sec) 0.2 3 4
Minimum time between onsets (sec) 5 0.33 0.25
Maximum time between onsets (sec) 90 2.0 3.3
Sleep present Yes Not required Not required
ALMA = alternating leg movement activity; EMG = electromyogram; HFT = hypnagogic foot tremor; LMs = leg movements; PLMs = periodic leg movements.

F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Nasal pressure

Airflow

Chest

Abdomen

RAT
LAT
SpO2
95 95 94 94 94 94 94 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93 93
93%

FIGURE 129 Excessive fragmentary myoclonus (EFM). A 30-second epoch with fragmentary myoclonus during nonrapid eye movement (NREM) sleep. In this
patient, 30 minutes of similar activity were noted meeting criteria for EFM. ECG = electrocardiogram; LAT = left anterior tibialis; RAT = right anterior tibialis;
SpO2 = pulse oximetry.

fingers and toes seen intermittently during REM sleep in TABLE 128
normal individuals. To qualify for EFM, the EMG pattern Scoring Criteria for Excessive
often seen during REM sleep must also be seen during non Fragmentary Myoclonus
rapid eye movement (NREM) sleep (Table 128). These rules define EFM:
1. The usual maximum EMG burst duration seen in EFM
events is 150 msec.
BRUXISM 2. At least 20 minutes of NREM sleep with EFM must be
Bruxism is a grinding or clinching of the teeth1,3,7 (Fig. 12 recorded.
10). It is associated with characteristic rhythmic muscle arti- 3. At least 5 EMG potentials/min must be recorded.
fact in the EEG (rhythmic EMG activity of the scalp muscle Note: Twitchlike movements in fingers, toes, and corner of mouth may be
underlying the EEG electrodes) and chin EMG activity. seen but no gross movements.
During sleep, jaw contractions are either tonic (jaw clinch- EFM = excessive fragmentary myoclonus; EMG = electromyogram; NREM =
nonrapid eye movement.
ing) or phasic (intermittent bursts of activity) termed rhyth- From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
mic masticatory muscle activity (RMMA). Of note, a diagnosis of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
of bruxism consists of more than detection of RMMAthere Events: Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
American Academy of Sleep Medicine, 2007, pp. 4142.
must be audible tooth grinding (Table 129).
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 Chapter 12
100 V
F4-M1
1 sec
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 1210 An episode of bruxism. The sound of tooth grinding was heard during the episode. EMG = electromyogram.
TABLE 129
Sleep-Related Bruxism (ICSD-2)
A. The patient reports or is aware of tooth grinding sounds
or tooth clenching during sleep.
B. One of more of the following is present:
i. Abnormal wear of teeth.
ii. Jaw muscle discomfort, fatigue, or pain and jaw lock
upon awakening.
iii. Masseter muscle hypertrophy upon voluntary forceful
clenching.
C. The jaw muscle activity is not better explained by
another current sleep disorder, medical or neurologic
disorder, medication use, or substance use disorder.
PSG Criteria (not listed as essential ICSD-2 criteria but
outlined in explanatory text in the ICSD-2 manual):
At least 25 individual bursts/hr of sleep
or
Four bruxism episodes/hr of sleep.
There should also be at least two audible tooth
grinding episodes per sleep recording session in the
absence of abnormal EEG (epilepsy).
EEG = electroencephalogram; ICSD-2 = International Classification of Sleep
Disorders, 2nd ed; PSG = polysomnography.
Adapted from American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Bruxism is common in childhood (1417%) and less
prevalent in teenagers (12%), middle-aged adults (8%), and
older adults (3%). Bruxism tends to occur in families.
Approximately 20% to 50% of patients have at least one
family member with a history of bruxism.
PSG Characteristics of Bruxism
Bruxism can occur in any stage of sleep or at arousal from
sleep. It is most common in stage N1 and N2 and least
common during REM sleep. The ICSD-2 recommends audio
monitoring and monitoring of at least one masseter muscle
for the diagnosis of bruxism. PSG criteria were not listed as
essential diagnostic criteria for bruxism in the ICSD-2.
Monitoring of Limb Movements and Other Movements during Sleep 183
TABLE 1210
Scoring Manual Rules for Bruxism
1. Bruxism may consist of brief (phasic) or sustained (tonic)
elevations of chin EMG activity that are at least twice the
amplitude of the background EMG.
2. Brief elevations of chin EMG activity are scored as bruxism
if they are 0.252 sec in duration and if at least three
such elevations occur in a regular sequence.
3. Sustained elevations of chin EMG activity are scored as
bruxism if the duration > 2 sec.
4. A period of at least 3 sec of stable background chin EMG
must occur before a new episode of bruxism can be
scored.
5. Bruxism can be scored reliably by audio in combination
with PSG by a minimum of two audible tooth grinding
episodes/night of PSG in the absence of epilepsy.
EMG = electromyogram; PSG = polysomnography.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
Events: Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
American Academy of Sleep Medicine, 2007, pp. 4142.
However, in the explanatory text, PSG criteria included at
least 25 individual bursts/hr of sleep or 4 bruxism episodes/
hr of sleep. It was also stated that there should also be at least
two episodes in which tooth grinding is heard on audio
monitoring in the absence of epilepsy. The AASM scoring
manual provides updated scoring criteria for bruxism (Table
1210). The scoring rules indicate that the chin EMG activity
must be at least twice the amplitude of the background EMG.
At least three elevations of EMG activity that are 0.25 to 2
seconds in duration should be present. For sustained EMG
elevations to be scored as bruxism, the duration must be
more than 2 seconds.
Whereas rhythmic EMG activity in the chin electrodes
can often be noted during bruxism episodes, such activity is
often more prominent if EMG recording over the masseter
muscles is performed. In some patients, bruxism may actu-
ally be more apparent from muscle artifact in the EEG and
electro-oculogram (EOG) derivations than in the chin EMG.
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184 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep
TABLE 1211
Prevalence of Rhythmic Movements
AGE FREQUENCY OF RMs
9 mo 59% of infants reported to have some type of RM
Body rocking (43%)
Head banging (22%)
Head rolling (24%)
18 mo 33% have some type of RM
5 yr 5% still have some type of RM
RMs = rhythmic movements.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
In Figure 1210, one can see rhythmic contractions of the
chin EMG and also muscle artifact in the EEG and EOG
derivations. During this episode, loud tooth grinding was
heard.
RHYTHMIC MOVEMENTS AND THE
SLEEP-RELATED RHYTHMIC
MOVEMENT DISORDER
Rhythmic movements (RMs) are common in normal infants
and children1517 (Table 1211). Without significant evidence
of consequences, the movements alone would not be con-
sidered a disorder. The term rhythmic movement disorder
(RMD) implies consequences are present. The ICSD-2 ter-
minology is sleep-related rhythmic movement disorder
(SRRMD).1 The ICSD-2 diagnostic criteria for the SRRMD
are listed in Table 1212. Adverse consequences in making
the diagnosis of SRRMD include interference with normal
sleep, daytime sleepiness or sleep disturbance, and bodily
injury to the patient (or potential bodily injury if preventive
measures were not taken).
Several clinical subtypes of RMD are noted including
body rocking type, head banging type, head rolling type, and
combined type.
PSG Findings in RM
The literature concerning RM varies1,1517 with some refer-
ences stating that RMs occur at sleep-wake transitions,16
whereas others state that RMs are more common in stage
N2.1 The ICSD-2 manual1 states that RM usually occurs
during stage N2, can occur during N3, or occurs only in
stage R. In some patients, RMs occur primarily during sleep-
wake transitions. In most patients, the EEG shows normal
activity between episodes of rhythmic behavior (although
often obscured by movement artifact).
The AASM scoring manual3 provides criteria for scoring
RMs (Table 1213). The frequency of movements is between
0.5 and 2.0 Hz. At least four movements must be present
to define a cluster of RMs. The minimum amplitude of
individual bursts is twice the background EMG activity
TABLE 1212
Sleep-Related Rhythmic Movement Disorder
(ICSD-2)
A. The patient exhibits repetitive, stereotyped, and
rhythmic movement behaviors.
B. The movements involve large muscle groups.
C. The movements are predominantly sleep related,
occurring near nap or bedtime, or when the individual
appears drowsy or sleepy.
D. The behaviors result in a significant complaint
manifested by at least one of the following:
i. Interference with normal sleep.
ii. Significant impairment of daytime function.
iii. Self-inflicted bodily injury that requires medical
treatment (or would result in injury if preventable
measures were not used).
E. The rhythmic movements are not better explained by
another current sleep disorder, medical or neurologic
disorder, mental disorder, medication use, or substance
use disorder.
CLINICAL SUBTYPES OF RMD
Body rocking type
Head banging type
Head rolling type
Other type: body rolling, leg rolling, leg banging
Combined type: involves one or more subtypes.
ICSD = International Classification of Sleep Disorders, 2nd ed; RMD =
rhythmic movement disorder.
Adapted from American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
TABLE 1213
Scoring Rules for the Polysomnography Features*
of the Rhythmic Movement Disorder
These rules defines the PSG characteristics of RMD
1. The minimum frequency for scoring RMD is 0.5 Hz.
2. The maximum frequency for scoring RMD is 2.0 Hz.
3. The minimum number of individual movements required
to make a cluster of rhythmic movements is four.
4. The minimum amplitude of an individual rhythmic burst
is twice the background EMG activity.
*Note: To be considered a DISORDER, a related complaint in addition to the
body movements must be present.
EMG = electromyogram; RMD = rhythmic movement disorder.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy
of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated
Events: Rules, Terminology and Technical Specification, 1st ed. Westchester, IL:
American Academy of Sleep Medicine, 2007, pp. 4142.
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 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep 185

100 V
1 sec F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG

Snore
Nasal pressure
Nasal-oral
thermal flow A
Chest
Abdomen

RAT
LAT
SpO2
99 99 99 99 99 99 99 99 99 99 99 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98 98

FIGURE 1211 Head banging, a form of rhythmic movement (RM) disorder. A 60-second tracing of a 5-year-old child. The RMs are seen as rhythmic activity in
multiple tracingsespecially prominent here in the leg tracings and E1-M2. This is stage W with RM stopping at point A. ECG = electrocardiogram; EMG =
electromyogram; LAT = left anterior tibialis; RAT = right anterior tibialis; SpO2 = pulse oximetry.

(Fig. 1211). The scoring manual recommends that bipolar
surface electrodes be placed to record large muscle group
involvement. However, time-synchronized video PSG is nec-
essary to make the diagnosis of RMD. For most patients, no
treatment for SRRMD is needed. In others with violent
movements, bed padding may be necessary. The disorder can
persist into childhood and adulthood. In some studies, an
association between RMD and attention deficit hyperactivity
disorder has been found in school-age children.16
RBD: SCORING PSG FEATURES
The RBD requires PSG evidence of REM sleep without atonia
and either video PSG showing dream-enacting behavior or
a compatible clinical history of episodes of dream-enacting
behavior (Table 1214).1,3,7,18 The sustained muscle activity of
the chin EMG or transient muscle activity of the chin or leg
EMG is interrupted by episodes of dream-enacting behavior.
The AASM scoring manual presents a system for defining
excessive sustained chin EMG activity or excessive transient
muscle activity in the chin or leg EMG derivations1,1821
(Table 1215). Figure 1212 is a 30-second tracing with
periods of sustained chin EMG activity as well as excessive
transient muscle activity in the leg EMG. Sustained chin
EMG activity is defined as an epoch of REM sleep with at
least 50% of the epoch having a chin amplitude greater than
the minimum amplitude in NREM sleep. Excessive transient
muscle activity in the leg EMG is defined as an epoch having
at least 5 of the 10 sequential 3-second miniepochs contain-
ing bursts of transient muscle activity. Excessive transient
muscle activity bursts are 0.1 to 5.0 seconds in duration
and at least four times as high in amplitude as the back-
ground EMG activity. Figure 1213 presents a 30-second
TABLE 1214
Rapid Eye Movement Sleep Behavior Disorder
(ICSD-2)
A. Presence of REM sleep without atonia: the EMG finding
of excessive amounts of sustained or intermittent
elevation of submental EMG tone or excessive phasic
submental or (upper or lower) limb EMG twitching.
B. At least one of the following is present:
i. Sleep-related injurious, potentially injurious, or
disruptive behavior by history.
ii. Abnormal REM sleep behavior documented during
PSG monitoring.
C. Absence of EEG epileptiform activity during REM sleep
unless RBD can be clearly distinguished from any
concurrent REM sleep-related seizure disorder.
D. The sleep disturbance is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, or substance use disorder.
EMG = electromyogram; ICSD = International Classification of Sleep Disorders,
2nd ed; PSG = polysomnography; RBD = rapid eye movement sleep behavior
disorder; REM = rapid eye movement.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
epoch of stage R (REM) with typical low-amplitude chin
EMG activity but excessive transient muscle activity in the
leg EMG derivations.
In frequently asked questions (FAQ) M1 (http://
www.aasmnet.org/Resources/PDF/FAQsScoringManual.
pdf), the following question was asked: In scoring the PSG
features of RBD, how many epochs of REM sleep must show
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186 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep

TABLE 1215
Scoring Rules for the Polysomnography Features* Associated with the Rapid Eye Movement Sleep
Behavior Disorder
RULES
1. The PSG characteristics of RBD are characterized by either or both of the following features:
a. Sustained muscle activity in REM sleep in the chin EMG.
b. Excessive transient muscle activity during REM in the chin or limb EMG.
DEFINITIONS
Sustained muscle activity in REM sleep is defined as an epoch of REM sleep with at least 50% of the duration of the epoch
having a chin EMG amplitude greater than the minimum amplitude in NREM.
Excessive transient muscle activity in REM sleep: In a 30-second epoch of REM sleep divided into 10 sequential 3-sec
miniepochs, at least five (50%) of the miniepochs contain bursts of transient muscle activity. In RBD, excessive transient
muscle activity bursts are 0.15.0 sec in duration and at least four times as high in amplitude as the background EMG activity.
*Note: PSG features ALONE are not sufficient to diagnose RBD.
EMG = electromyogram; NREM = nonrapid eye movement; PSG = polysomnography; RBD = rapid eye movement sleep behavior disorder; REM = rapid eye
movement.
From Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and Associated Events:
Rules, Terminology and Technical Specification, 1st ed. Westchester, IL: American Academy of Sleep Medicine, 2007, pp. 4142.

100 V
F4-M1
1 sec C4-M1
O2-M1
E1-M2
E2-M2

Chin EMG
ECG

RAT
LAT

FIGURE 1212 A 30-second tracing of stage R with transient muscle activity seen in the right anterior tibialis (RAT) and left anterior tibialis (LAT). Sustained muscle
activity in the chin electromyogram (EMG) is noted in the last two thirds of the epoch. The RAT and LAT activity also meets criteria for excessive transient muscle
activity. ECG = electrocardiogram.

100 V
F4-M1
1 sec C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG

ECG

RAT
LAT

FIGURE 1213 Another 30-second epoch in the same patient presented in Figure 1212. Here, the chin electromyogram (EMG) is typical of stage R but the right
DaneshGroup.com
anterior tibialis (RAT) and left anterior tibialis (LAT) show excessive transient muscle activity. ECG = electrocardiogram.
 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep
either sustained or excessive transient muscle activity for
REM sleep as a whole to be considered compatible with
RBD? The answer was the manual has deliberately not spec-
ified this as there are little normative data. Clinicians are
encouraged to read the relevant section of the supporting
paper7 to help them decide how to address this issue in their
own laboratories. Certainly, a relatively large number of
epochs with sustained or excessive transient EMG activity
would be suggestive of RBD. Conversely, fewer epochs with
intense EMG activity associated with characteristic body
movements would also be suggestive of a diagnosis of RBD.
In summary, patients with RBD can have characteristic find-
ings in the chin EMG, limb EMGs (e.g., RAT and LAT), or
both. Clinical correlation is needed. The RBD is discussed in
more detail in Chapter 28.
CLINICAL REVIEW QUESTIONS
1. Frequent LMs during wake as documented by the ante-
rior tibial derivations is most suggestive of:
A. PLMD.
B. PLMS.
C. RLS.
2. A diagnosis of PLMD requires:
A. Adult PLMSI > 5/hr, pediatric PLMSI > 5/hr.
B. Adult PLMSI > 15/hr, pediatric PLMSI > 15/hr.
C. Adult PLMSI > 10/hr, pediatric PLMSI > 5/hr.
D. Adult PLMSI > 15/hr, pediatric PLMSI > 5/hr.
3. The duration of a significant LM is:
A. 0.55 sec.
B. 0.510 sec.
C. 110 sec.
D. 0.515 sec.
4. According to the AASM scoring manual, the minimum
amplitude of a significant LM is:
A. 25% of the baseline leg EMG.
B. 50% of the baseline leg EMG.
C. >8 V above baseline limb EMG activity.
D. >10 V above baseline limb EMG activity.
5. A diagnosis of EFM requires that fragmentary myoclonus
be present for at least:
A. 20 min of REM sleep.
B. 10 min of NREM sleep.
C. 20 min of NREM sleep.
D. 10 min of REM sleep.
6. A diagnosis of SRRMD requires:
A. Movements must occur during sleep.
B. Behaviors result in a significant complaint (impaired
daytime function, bodily injury, interference with
normal sleep).
187
C. The minimum and maximum frequency of move-
ments must be 13 Hz.
Answers
1. C. The diagnosis of RLS is based on clinical history but
frequent LMs during wake (as during a prolonged sleep
latency) are suggestive of the diagnosis.
2. D.
3. B.
4. C.
5. C.
6. B. To be diagnosed as a disorder, complaints must be
present. Frequency of movements is 0.52 Hz. Move-
ments can occur during sleep-wake transitions.
REFERENCES
1. American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and
Coding Manual. Westchester, IL: American Academy of Sleep
Medicine, 2005.
2. Coleman RM: Periodic movements in sleep (nocturnal myoc-
lonus) and restless legs syndrome. In Guilleminault C (ed):
Sleeping and Waking Disorders: Indications and Techniques.
Boston: Butterworths, 1982, pp. 265295.
3. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring
of Sleep and Associated Events: Rules, Terminology and Tech-
nical Specification, 1st ed. Westchester, IL: American Academy
of Sleep Medicine, 2007, pp. 4142.
4. American Sleep Disorders Association: International Classifi-
cation of Sleep Disorders, 1st ed. Rochester, MN: American
Sleep Disorders Association, 1990, pp. 6568.
5. American Sleep Disorders Association: Recording and scoring
leg movements. The Atlas Task Force. Sleep 1993;16:748759.
6. Zucconi M, Ferri R, Allen R, et al: The official World Associa-
tion of Sleep Medicine (WASM) Standards for Recording and
Scoring Periodic Leg Movements in Sleep (PLMS) and Wake-
fulness (PLMW) developed in collaboration with a task force
from the International Restless Legs Syndrome Study Group
(IRLSSG). Sleep Med 2006;7:175183.
7. Walters AS, Lavigne G, Hening W, et al: The scoring of move-
ments in sleep. J Clin Sleep Med 2007;3:155167.
8. Montplaisir J, Boucher S, Nicholas A, et al: Immobilization tests
and periodic leg movements in sleep for the diagnosis of rest-
less legs syndrome. Mov Disord 1998;13:324329.
9. Montplaisir J, Boucher S, Poirer G, et al: Clinical, polysomno-
graphic, and genetic characteristics of restless legs syndrome: a
study of 133 patients diagnosed with the new standard criteria.
Mov Disord 1997;12:6165.
10. Chervin RD, Consens FB, Kutluay E: Alternating leg muscle
activation during sleep and arousals: a new sleep-related motor
phenomenon? Mov Disord 2003;18:551559.
11. Berry RB: A woman with rhythmic foot movements. J Clin
Sleep Med 2007;3:749751.
12. Constantino FI, Iero I, Lanuzza B, et al: The neurophysiology
of the alternating leg muscle activation (ALMA) during study
of one patient before and after treatment with pramipexole.
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188 Chapter 12 Monitoring of Limb Movements and Other Movements during Sleep
13. Broughton R, Tolentino MA, Krelina M: Excessive fragmentary
myoclonus in NREM sleep: a report of 38 cases. Electroen-
cephalogr Clin Neurophysiol 1985;6:123133.
14. Vetrugno R, Piazzi G, Provini F, et al: Excessive fragmentary
hypnic myoclonus: clinical and neurophysiological findings.
Sleep Med 2001;3:7376.
15. Hoban TF: Rhythmic movement disorder in children. CNS
Spectr 2003;8:135138.
16. Stepanova I, Nevsimalova S, Hanusova J: Rhythmic movement
disorder in sleep persisting into childhood and adulthood.
Sleep 2005;28:851857.
17. Kohyama J, Matsukura F, Kimura K, Tachibana N: Rhythmic
movement disorder: polysomnographic study and summary of
reported cases. Brain Dev 2002;24:3338.
18. Lapierre O, Montplaisir J: Polysomnographic features of REM
sleep behavior disorder: development of a scoring method.
Neurology 1992;43:13711374.
19. Consens F, Chervin RD, Koeppe RA, et al: Validation of poly-
somnographic score for REM sleep behavior disorder. Sleep
2005;28:993997.
20. Sforza E, Krieger J, Petiau C: REM sleep behavior: clinical and
physiopathological findings. Sleep Med Rev 1997;1:5769.
21. Eisensehr I, Lindeiner H, Jager M, Noachtar S: REM sleep
behavior disorder in sleep-disordered patients with versus
without Parkinsons disease: is there a need for polysomnogra-
phy? J Neurol Sci 2001;186:711.
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Polysomnography,
Portable Monitoring,
and Actigraphy
Chapter Points
PSG is indicated for evaluation of suspected OSA and
for PAP titration. PSG is indicated for preoperative
evaluation for planned surgery (to treat OSA or
snoring), and postoperatively to document surgical
effectiveness.
PSG is indicated to document effectiveness of oral
appliance treatment of OSA. The practice parameters
for oral appliance therapy state that a diagnostic study
should be performed if an oral appliance is planned
for snoring or suspected OSA.
PSG is indicated for evaluation of OSA patients being
treated with CPAP or an oral appliance in whom
symptoms have returned (PSG using CPAP or OA).
PSG is indicated if there is a clinical suspicion of OSA
in patients with heart failure, coronary artery disease,
recent or past stroke or transient ischemic attack, and
neuromuscular disorders.
A repeat PSG is indicated if an initial study is negative
but there is a high index of suspicion for OSA.
A PSG is indicated if there is weight loss (>10%) of an
OSA patient on CPAP to determine whether CPAP is
still indicated.
A PSG is indicated in a patient using CPAP after weight
gain (>10%) to determine whether higher pressure is
needed.
A PSG is NOT indicated for evaluation of the restless
legs syndrome, insomnia, uncomplicated parasomnias,
COPD, or a patient doing well on CPAP treatment.
Attended PM can be used as an alternative to PSG to
diagnose OSA when there is a high pretest probability
and to determine the effectiveness of therapy.
Attended PM (type 3) is indicated if treatment is
urgent and PSG is delayed or the patient cannot have
a PSG in the sleep center owing to immobility or safety
issues.
Chapter 13
An unattended PM (type 3) is indicated to diagnose
OSA in patients with a high probability of having
moderate to severe OSAIF combined with a
comprehensive sleep evaluation and significant
co-morbid medical disorders or sleep disorders that
would benefit from PSG are excluded. A negative PM
study should be followed by a PSG in most cases (to
be studied by PM, there must be a high probability of
having moderate to severe OSA).
Review of the raw PM data is essential to verify
adequate technical quality of a study and to determine
whether the respiratory events were properly scored.
The AASM PMGs recommended at a minimum airflow,
respiratory effort, and oxygen saturation should be
monitored.
Qualified providers should either place the PM sensors
or instruct the patients to avoid a high proportion of
technically inadequate studies.
Selection of the PM device should take into account
the setting in which it will be used and whether the
patient will place the sensors without assistance at
home.
POLYSOMNOGRAPHY
The American Academy of Sleep Medicine (AASM) prac-
tice parameters16 outline the indications for polysomnogra-
phy (PSG) (Tables 131 to 134 and Appendix 131). PSG
is the standard test for diagnosis of suspected sleep-related
breathing disorders (SRBDs), narcolepsy (when combined
with a multiple sleep latency test [MSLT]), positive airway
pressure (PAP) titration, and evaluation of parasomnias
(under certain conditions).2,6 PSG is also indicated to
document the efficacy of prior surgical treatment and deter-
mine the efficacy of oral appliance (OA) treatment (PSG
while wearing the OA).2,6 The 2005 practice parameters for
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190 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
TABLE 131
Indications for Polysomnography (Sleep-Related
Breathing Disorders)
DIAGNOSTIC PSG
Diagnosis of suspected sleep-related breathing disorders
(OSA, central sleep apnea).
Preoperative PSG before planned surgery for snoring or
OSA (attended cardiorespiratory [type 3 PM] study is also
acceptable).
REPEAT PSG
Repeat PSG is indicated if the initial PSG was negative +
there is a high clinical suspicion for OSA.
After 10% weight loss in a patient on CPAP to see
whether CPAP is still needed (if clinically indicated).
FOLLOW-UP PSG (NON-PAP TREATMENT)
After surgery for moderate to severe OSAusually
36 mo after surgery (most would also study patients
with mild OSA).
After previous surgery for OSA if symptoms return.
After adequate adjustment of oral appliance for OSA (all
severities*) (PSG using OA).
*Amended by practice parameters for oral appliance treatment to include all
severities of OSA.6
Cardiorespiratory study = four channels, airflow, effort (or two effort
channels), oxygen saturation, and ECG or heart rate.
ECG = electrocardiogram; OSA = obstructive sleep apnea; PAP = positive
airway pressure; PM = portable monitoring; PSG = polysomnography.
PSG stated that attended cardiorespiratory pulmonary
studies (airflow + effort or two effort channels, oximetry,
and electrocardiogram [ECG] or heart rate) are an accept-
able alternative to PSG for diagnosis of obstructive sleep
apnea (OSA) in patients with high pretest probability of
OSA2,7 or for determining the adequacy of prior surgery for
OSA or effectiveness of current OA treatment.2,6,7 In 2007,
the AASM published Clinical Guidelines for the Use of Por-
table Monitoring in Evaluation of Adult Patients with OSA8
(hereafter referred to as PMGs). The PMGs state that unat-
tended portable monitoring (PM) may be acceptable to
monitor patients with a high probability of having moderate
to severe OSA, if monitoring is performed according to
the guidelines. Unattended PM monitoring is also accept-
able for assessing the efficacy of non-PAP treatment of OSA.
The Centers for Medicare and Medicaid Services (CMS)
now recognize a diagnosis of OSA by unattended PM as
acceptable for reimbursement of continuous positive airway
pressure (CPAP) treatment9 and considers unattended PM
studies reimbursable provided certain conditions are met.10
PSG for Patients with SRBDs (see Table 131)
PSG is the standard diagnostic study for evaluation of a
suspected SRBD. A diagnostic study may be repeated if the
TABLE 132
Indications for Polysomnography (Positive Airway
Pressure Titration and Treatment)
PAP TITRATION
Patients: AHI 15/hr with or without symptoms, AHI 5/
hr with symptoms.
Full night of PSG titration.
Split studyif at least 3 hr remain for titration
AHI > 40 during 2 hr of monitoring in the initial
diagnostic portion.
AHI 2040 special clinical circumstances (long apnea/
severe desaturation).
3 hr remain for PAP titration.
Repeat PSG for PAP titration if inadequate PAP titration
portion of study
REPEAT PSG ON CPAP
After 10% weight gain to determine whether CPAP is
adequate (if clinically indicated).
Clinical symptoms return in patient on CPAP (consider
PSG + MSLT if narcolepsy is suspected).
REPEAT PSG ON CPAP NOT INDICATED
Routine follow-up of a patient doing well on PAP
treatment.
Type 3 (cardiorespiratory study) = four channels, airflow, effort (or two effort
channels), oxygen saturation, and ECG or heart rate.
AHI = number of apneas + hypopneas/hr of sleep.
AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure;
ECG = electrocardiogram; MSLT = multiple sleep latency test; OSA =
obstructive sleep apnea; PAP = positive airway pressure; PSG =
polysomnography.
From Kushida CA, Morgenthaler T, Littner MR, et al: Practice parameters for
the treatment of snoring and obstructive sleep apnea with oral appliances:
an update for 2005. Sleep 2006;29:240243.
initial study was negative for sleep apnea and there is a high
clinical index of suspicion for this disorder. PSG should be
performed preoperatively for planned surgery to treat
snoring or suspected OSA.1,2 PSG is indicated for snoring
because an appreciable number of patients will also have
OSA. A PSG is indicated after surgery for OSA (after surgical
healing) to document effectiveness. The practice parameters
specify in moderate to severe OSA, although most clini-
cians would perform a PSG after surgery for mild OSA as
well.
Determination of the presence of OSA is indicated for
planned OA treatment of snoring or suspected OSA.6 The
type of diagnostic procedure was not specified in the practice
parameters for OAs. However, PSG is always indicated to
diagnose OSA. PSG is indicated after adjustment of an OA
for OSA (not for primary snoring) to document efficacy. The
2007 practice parameters for PSG recommended a sleep
study with the patient using an OA for treatment of moder-
ate to severe OSA to document efficacy.2 In a subsequent
practice parameter on OA treatment of OSA, a PSG to docu-
ment efficacy was recommended for OSA of all severities.6
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 Chapter 13
TABLE 133
Indications for Polysomnography in
Nonrespiratory Sleep Disorders
NARCOLEPSY
PSG INDICATED
Before MSLT for diagnosis of suspected narcolepsy.
PARASOMNIAS OR SEIZURE DISORDER
PSG INDICATED
Nocturnal seizure is suspected (undiagnosed).
Presumed parasomnia/nocturnal seizure disorder does
not respond to conventional treatment.
Presumed parasomnia is injurious to the patient or others
(or is potentially injurious) or follows trauma or with
forensic (legal) implications.
Presumed parasomnia has atypical features (stereotypic
behavior, frequent events per night, atypical age of
onset).
PSG NOT INDICATED
Typical, noninjurious behavior for which clinical
evaluation is sufficient.
Known seizure disorder patient without nocturnal
complaints.
SLEEP-RELATED MOVEMENT DISORDER
PSG INDICATED
For suspected periodic limb movement disorder.
PSG NOT INDICATED
Evaluation and treatment of RLS.
INSOMNIA
PSG NOT INDICATED (Patients Complaining of Insomnia)
Routine evaluation of transient insomnia, chronic
insomnia, or insomnia associated with psychiatric
disorders.
PSG INDICATED (Patients Complaining of Insomnia)
Sleep-related breathing disorder is suspected.
Periodic limb movement disorder is suspected.
Initial diagnosis is uncertain.
Treatment of insomnia fails (behavioral or pharmacologic).
Precipitous arousals occur with violent or dangerous
behavior.
MSLT = multiple sleep latency test; PSG = polysomnography; RLS = restless
legs syndrome.
For patients with prior effective surgical treatment (docu-
mented by PSG), the PSG may be repeated at a later time if
symptoms of sleep apnea return. For a patient using an OA
as treatment for OSA, the PSG may also be repeated while
the patient wears the OA if the patients symptoms return. If
a patient on CPAP loses more than 10% of body weight, a
Polysomnography, Portable Monitoring, and Actigraphy 191
TABLE 134
Summary of Circumstances in Which
Polysomnography Is NOT Indicated
Routine evaluation of a patient doing well on CPAP
treatment.
Evaluation of asthma or chronic lung disease (unless OSA
is suspected).
Routine evaluation of insomnia.
Evaluation and treatment of RLS (unless the periodic limb
movement disorder is suspected).
Evaluation of uncomplicated parasomnias for which a
clinical diagnosis is sufficient.
Evaluation of a circadian rhythm sleep disorder.
CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea;
RLS = restless legs syndrome.
diagnostic PSG is indicated to determine whether CPAP is
still needed. This assumes the test is clinically indicated
based on evaluation of the patients overall clinical status and
the likelihood of weight loss maintenance.
The 2005 practice parameters for PSG also mentioned a
number of circumstances in which SRBDs are very common.2
However, PSG is NOT routinely indicated in those circum-
stances unless a clinical evaluation reveals a reasonable
suspicion for SRBD. The disorders discussed included
patients with systolic or diastolic heart failure, recent or
past stroke or transient ischemic attack (TIA), coronary
artery disease, and tachyarrhythmias or bradyarrhyth-
mias. Most clinicians would also place resistant hyperten-
sion or pulmonary hypertension of unknown etiology in this
category as well. The clinician should recognize that many
patients with significant OSA do not complain of daytime
sleepiness. A history of snoring and gasping would suggest
a PSG is indicated. It should also be noted that some patients
with OSA complain of insomnia. The practice parameters do
list neuromuscular diseases as a group of disorders in which
PSG is indicated for evaluation of sleep-related symptoms.
Routine evaluation of chronic lung disease is not an indica-
tion for PSG unless coexistent OSA is suspected. Nocturnal
oximetry is a useful tool for determining whether nocturnal
oxygen desaturation is occurring in a patient with chronic
obstructive pulmonary disease (COPD). A saw-tooth pattern
is suggestive of sleep apnea.
PSG Titration and PSG on CPAP (see Table 132)
A PSG for PAP titration is the standard procedure to select
a level of pressure for treatment.1,2,11 The titration can be
performed on a separate night after a diagnostic PSG or
during the second part of the night during a split (partial-
night) study. A split sleep study is recommended when (1)
the diagnostic portion shows an apnea-hypopnea index
(AHI) greater than 40/hr with at least 2 hours of monitoring,
(2) there is an AHI of 20 to 40 with special clinical
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192 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
circumstances such as severe desaturation or arrhythmia
thought due to OSA, and (3) at least 3 hours remain for the
PSG titration.1,2,11,12 If the PSG titration does not last at least
3 hours or is not adequate, a repeat PSG titration is indicated.
PSG PAP titration techniques and PAP treatment are dis-
cussed in Chapter 19. Of note, financial constraints may
require use of less stringent split study criteria.
PSG is NOT recommended in patients on CPAP treat-
ment who are doing well. If the patient is being treated on
CPAP and is NOT doing well, a repeat PSG study on CPAP
is indicated.2 However, before this expensive procedure,
it is essential to document adequate objective adherence and
to optimize treatment and the mask interface. PSG is also
indicated if a patient on CPAP gains more than 10% of
body weight to determine whether the pressure is adequate.
However, a repeat PSG titration may not be clinically
indicated.
PSG Indications: Nonrespiratory Disorders
PSG Indicated (see Tables 133 and 134)
A PSG preceding an MSLT is indicated for evaluation of
suspected narcolepsy or to help differentiate narcolepsy
from idiopathic hypersomnia.13 PSG is indicated for evalu-
ation of suspected periodic limb movement disorder but
NOT the restless legs syndrome (RLS; a clinical diagnosis).
A PSG with extended (and bilateral) electroencephalogram
(EEG) derivations and video monitoring is indicated to eval-
uate (1) nocturnal behavior possibly due to seizures, (2)
atypical parasomnia behavior (frequent episodes each night,
stereotypic behavior, or behavior unusual for age), (3) noc-
turnal behavior/parasomnia that has resulted in injury to the
patient or others (or has the potential to do so), (4) presumed
parasomnia or nocturnal seizure disorder that does not
respond to conventional treatment, or (5) if there are legal/
forensic implications of nocturnal behavior.2 The practice
parameters recommend looking at events in a 10-second
window to observe for seizure activity and consultation
with a physician with expertise in reading clinical EEGs
if necessary.
PSG NOT Indicated (see Tables 133 and 134)
PSG is not indicated for evaluation of insomnia (unless OSA
is suspected) or unless insomnia does not respond to usual
treatment. PSG is not indicated for diagnosis of depression
or insomnia with depression.2,4 The practice parameters for
use of PSG4 in evaluation of insomnia state PSG is indicated
when initial diagnosis is uncertain, treatment fails (behav-
ioral or pharmacologic), or precipitous arousals occur with
violent or injurious behavior (Guideline).
Although the PSG finding of a short rapid eye movement
(REM) latency is common in depression, this finding is not
sufficiently sensitive or specific to warrant a PSG in evaluat-
ing patients with suspected depression. A PSG is NOT indi-
cated for (1) typical uncomplicated and noninjurious
parasomnias when the diagnosis is clearly delineated or
(2) patients with known seizure disorders who have no
nocturnal complaints. Table 134 is a summary of the cir-
cumstances in which PSG is not indicated.
Approach to the Sleepy Patient
on PAP Treatment
If a patient with OSA continues to have daytime sleepiness
on adequate PAP treatment (documented adequate adher-
ence and adequate control of respiratory events), there are
two options. As discussed in Chapter 18 on medical treat-
ment of OSA, an alerting agent such as modafinil may be
added.13 If there is a suspicion of narcolepsy in addition to
OSA, a nocturnal PSG on PAP treatment (documenting
adequate treatment) followed by an MSLT on PAP can be
performed (see Chapters 14 and 24). If unambiguous cata-
plexy is present, the patient likely has narcolepsy and the
MSLT is simply confirmatory. It is essential that adequate
PAP treatment for OSA be confirmed before expensive
testing. This includes documentation of adequate objective
adherence. Many PAP devices also have the ability to
record residual AHI. A high residual AHI would be an indi-
cation for an adjustment in pressure (empirical increase) or
a PSG PAP titration.1,2 The PAP device estimate of residual
AHI is not always accurate, but a high value has a reasonable
positive predictive value that the residual AHI is indeed
elevated.14 A surprising number of patients (up to 15%) on
chronic PAP treatment are not adequately treated (AHI >
10/hr).15,16
Approach to Reading the PSG
Before the PSG is read, a review of the clinical history with
special attention to symptoms of sleep apnea, narcolepsy,
RLS, and medications is very useful. The amount of chronic
alcohol intake and the medications actually taken before the
sleep study should be noted. The presence of underlying lung
disease may help explain a low awake arterial oxygen satura-
tion (SaO2) or low baseline sleeping SaO2. A clinical history
of pacemaker insertion or known atrial fibrillation is also
very helpful in providing a useful interpretation of ECG
findings. If a PAP titration is planned for a patient currently
using CPAP, the current treatment pressure level should be
noted. During the reading of the PSG, a return to the clinical
history may be helpful (Table 135).
All digital PSG systems have a view that shows graphical
summary information of the entire night (Fig. 131 and
Table 136). It is often useful to look at the big picture before
going through the data in smaller time windows. The bio-
calibrations are often helpful in noting the appearance of
eyes-open wake in a given patient and whether the patient
produces an alpha rhythm with eye closure (see Chapters 3
and 4).
PORTABLE MONITORING (HOME SLEEP
TESTING, OUT OF CENTER SLEEP TESTING)
PM, also called home sleep testing (HST) or out of center
sleep testing (OCST), has been the subject of intense interest
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 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 193

TABLE 135
Historical Elements to Review Based on Polysomnography Findings
EEG/EOG/EMG
Long sleep latency?history of insomnia
Short REM latency?history of symptoms of narcolepsy, cataplexy, or depression
Alpha sleep?chronic pain syndrome or psychiatric disorders
Persistent eye movements during stage N2?SSRI medication
Increased spindle activity?benzodiazepines (regular medication or special medication before sleep study)
Transient muscle activity (chin EMG) activity during stage R?SSRI treatment, history of dream enactment
Arousals from stage N3 with body movement?history of NREM parasomnia
Body movement and speech during REM sleep?history suggestive of RBD
RESPIRATION
Low awake SaO2?presence of lung disease
Low sleeping baseline SaO2?presence of lung disease
Cheyne-Stokes breathing?history of congestive heart failure
Ataxic breathing, low respiratory rate?history of potent opiates
Delay in SaO2 nadir after respiratory events?decreased cardiac output
LEG MONITORING
Frequent LMs during wake?symptoms of RLS
High PLM indexcan be seen associated with OSA, PAP titration, RLS
Increased transient muscle activity during REM sleep?SSRI medications, history of dream enactment
ECG
Tachycardia in sleep (>90 bpm)?anxiety, stimulants
Bradycardia in sleep (<40 bpm)?beta blocker, ?known cardiac disorder
Atrial fibrillation?previously documented
Pacemaker?if wide complex QRS with normal rate (e.g., 6080)
? = consult history for relevant items.
ECG = electrocardiogram; EEG = electroencephalogram; EMG = electromyogram; EOG = electro-oculogram; LMs = limb movements; NREM = nonrapid eye
movement; PAP = positive airway pressure; PLM = periodic limb movement; RBD = rapid eye movement sleep behavior disorder; REM = rapid eye movement;
RLS = restless legs syndrome; SaO2 = arterial oxygen saturation; SSRI = selective serotonin reuptake inhibitor.

recently.17,18 The tests are not always performed in the home;
hence, the terms HST or PM are not ideal but are used in
much of the literature on this subject. The term PM is used
in this chapter. In the past, PM has been used to diagnose
OSA in settings in which access to PSG is limited or delayed.
The traditional classification of monitoring devices for the
diagnosis of sleep apnea was originated by Ferber and col-
leagues (Table 137).1921 This classification was used for the
Tri-Society PM evidence review,22 executive summary,23 and
practice parameters for the PM.7 The original classification
used level I, II, III, and IV to refer to different classes of
monitoring but currently the terminology is type 1, 2, 3, and
4. The Centers for Medicare and Medicaid Services (CMS)
has a different classification for monitoring (Table 138).9
The CMS terminology defines the respiratory disturbance
index (RDI) as the total number of apneas and hypopneas
per hour of monitoring time. Therefore, the index deter-
mined by PM (no EEG) would be an RDI using the CMS
definition. CMS also refers to PM as HST.
Developments in the Use of PM
Important developments in the history of PM are listed in
Table 139. AASM practice parameters in 1994,20 1997,1 and
20052 specified a limited role for attended PM. However,
unattended PM was widely used in locales in which access
to PSG was very limited. On the basis of a Tri-Society evi-
dence review for the use of PM,22 practice parameters pub-
lished in 20037 stated that certain type 3 PM devices used in
the attended setting could be used to rule in or rule out
OSA.7 Before 2008, the National Carrier Determination
(NCD) 240.4 on CPAP treatment specified a diagnosis of
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194 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy

100%
95%
SpO2 90%
85%
80%
75%
A B C
70%
Left
Right
Position
Prone
Supine

Respiratory event

Desaturation

Wake
Stage REM
1
2
3

Epoch 60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960
22:17:44 23 00 01 02 03 04 05 06 06:43:15
Time

FIGURE 131 Summary view shows three periods of significant arterial oxygen desaturations (A, B, and C) during rapid eye movement (REM) sleep. In addition, the
summary view shows that no supine REM sleep was recorded. SpO2 = pulse oximetry.

TABLE 136 Appendix 133, for example). In general, a physician Board-

Special Elements of Polysomnography to Note
during Interpretation
Technologist commentsespecially for epochs of abnormal
EEG or ECG or notable body movements.
Biocalibrationsobserve adequacy of tracings, sensor
function, production of alpha with eye closure, nature of
eyes-open wakefulness, correct polarity of nasal pressure
and chest and abdominal belts.
Overnight summary viewthe big picture of SaO2 and
hypnograms
REM-associated OSA.
Postural OSA.
Alternate between 30- and 90-second windows to observe
sleep and respirations.
10-second window for suspicious or abnormal EEG or ECG
activity.
ECG = electrocardiogram; EEG = electroencephalogram; OSA = obstructive
sleep apnea; REM = rapid eye movement; SaO2 = arterial oxygen saturation.
OSA must be made by attended PSG for subsequent CPAP
treatment to be reimbursed. There were several requests
for CMS to revise the policy to include PM (HST) devices.
The evaluation of PM changed from an analysis of accuracy
of PM compared with PSG to an analysis of PMs ability
to identify OSA patients who would benefit from treatment.
In 2007, the AASM published clinical guidelines for the use
of unattended PM8 (PMGs) (Appendix 132). In a 2008
ruling, CMS issued a decision allowing patients to qualify
for CPAP treatment on the basis of a diagnosis by HST pro-
vided certain guidelines are followed.9 The specific rules
vary according to local carrier determinations (LCDs; see
certified or Board-eligible (BC/BE) in sleep medicine or
associated with a sleep center accredited by the AASM or the
Joint Commission is allowed to interpret the HSTs. The
durable medical equipment (DME) providers are not allowed
to perform HST on patients that they will provide with PAP
equipment. In 2009, CMS published a decision stating that
PM testing itself would be reimbursable.10 The reimburse-
ment fees vary between locales but are very modest. The
AASM now offers accreditation for OCST.
Accuracy of PMs
The analysis of agreement between measurements from dif-
ferent devices is complex.22,24 A systematic review of agree-
ment between PSG and ambulatory sleep studies was
published in 2003.22 At that time, the best evidence for agree-
ment between PM and PSG was for type 3 PM studies in the
attended setting. The analysis focused on comparison of AHI
values. However, the major issue is ability of the PM-derived
AHI to correctly classify patients as having OSA and identi-
fying those patients who would benefit from treatment. For
example, AHI results of 30/hr versus 60/hr would both be
consistent with severe sleep apnea even though the AHI
values were quite different. Conversely, AHI results of 3
versus 13 would classify the patient as either being normal
or having mild OSA. Numerous studies have compared the
AHIs derived from PSG and PM devices. There are a number
of reasons why the AHIs from PSG and PM might differ
(Table 1310). In general, studies comparing PSG and PM
have either used simultaneous monitoring with PSG and PM
in the sleep center or compared PSG in the sleep center with
unattended PM on a different night at home. Both approaches
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 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 195

TABLE 137
Classification of Portable Monitoring*
TYPE 4: CONTINUOUS
TYPE 3: MODIFIED SINGLE OR DUAL
TYPE 1: ATTENDED TYPE 2: PORTABLE SLEEP APNEA BIOPARAMETER
PSG UNATTENDED PSG TESTING RECORDING
Measures Minimum of seven Minimum of seven Minimum of four, including Minimum of one
(channels) channels including channels including ventilation (at least two oxygen saturation,
ECG, EEG, EOG, chin EEG, EOG, chin channels of respiratory flow, or chest
EMG, airflow, EMG, heart rate or movement or respiratory movement
respiratory effort, ECG, airflow, movement and airflow),
oxygen saturation respiratory effort, heart rate or ECG, and
oxygen saturation oxygen saturation
Body position Documented or Possible Possible No
objectively measured
Leg movement EMG or motion sensor Optional Optional No
desirable but optional
Personnel Possible No No No
interventions
*Levels I, II, III, and IV monitoring are now termed types 1, 2, 3, and 4.
ECG = electrocardiogram; EEG = electroencephalogram; EMG = electromyogram; EOG = electro-oculogram; PSG = polysomnography.
From Ferber R, Millman R, Coppola M, et al: ASDA standards of practice: portable recording in the assessment of obstructive sleep apnea. Sleep 1994;17:378392.

TABLE 138
Centers for Medicare and Medicaid Services Classification of Portable Monitoring
HCPCS CODE TYPE SETTING MONITORING
G0398 2 Unattended Minimum of seven channels including EEG, EOG, EMG,
ECG/heart rate, oxygen saturation, anterior tibial EMG
G0399 3 Unattended Minimum of four channels and must record ventilation,
oximetry, and ECG or heart rate
G0400 4 Unattended Minimum of three channels, and one must be airflow
Unattended Minimum of three channels including peripheral arterial
tonometry, actigraphy, and oximetry
2011 Codes for PM Studies
95800 Sleep study, unattended, simultaneous recording; heart rate, oxygen saturation, respiratory analysis (e.g., by airflow or peripheral arterial tone), and sleep
time;
95801 Sleep study, unattended, simultaneous recording; minimum of heart rate, oxygen saturation, and respiratory analysis (e.g., by airflow or peripheral arterial
tone);
95806 Sleep study, simultaneous recording of ventilation, respiratory effort, ECG or heart rate, and oxygen saturation, unattended by a technologist.
Note: Some durable medical equipment (DMAC) providers still use G codes. The entire area is in flux. The reader should consult the CMS website or their local DMAC
provider for the latest information.
ECG = electrocardiogram; EEG = electroencephalogram; EMG = electromyogram; EOG = electro-oculogram; HCPCS = Healthcare Common Procedure Coding System.

are problematic. In either case, even if the same type of
sensors are used and the same number of events are identi-
fied, the two devices would still give different AHI values as
monitoring time (PM) would exceed total sleep time (PSG).
For example, if both methods detect 70 apneas and hypop-
neas, dividing by 5 hours of total sleep time (TST; AHI = 14/
hr) will give a higher index than dividing by 7 hours of
monitoring time (AHI = 10/hr). It is also possible that the
oximeters used in different systems could differ in their
ability to detect desaturations. Comparing PM and PSG AHI
values during simultaneous recording reduces the effects of
night-to-night variability. However, this does not mimic how
the devices are actually used. The different nightsdifferent
locations approach mimics real world conditions. However,
if the different nights approach is used to compare PSG and
PM, the AHI values could differ simply due to night-to-night
variability in the AHI.
In general for milder OSA, the amounts of REM and
supine sleep are the major determinants of the AHI. These
patients have elevated AHI mainly in the supine position or
during REM sleep. Table 1311 presents the effect of differ-
ent proportions of REM and supine sleep on the overall AHI
(assuming certain AHI values in different conditions). In
milder OSA patients, night-to-night differences in the
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196 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy

TABLE 139
History of Recent Developments in Portable Monitoring (Home Sleep Testing)
1994 Practice Parameter for Type 2 or type 3 PM is an acceptable alternative to PSG in the following circumstances:
Portable Monitoring20 1. Patients with severe clinical symptoms of OSA and when initiation of treatment is
urgent and PSG is not readily available.
2. Patient unable to be studied in sleep laboratory.
3. Diagnosis already established by PSG and treatment initiated and the purpose is
to evaluate response to treatment.
Tri-Society (ACCP, ATS, AASM) 2003 Attended type 3 studies may be used to rule in or rule out OSA provided certain
Evidence Review (Chest)22 limitations are met. These include manually scoring the records, using the device in
Executive Summary23 patients without significant co-morbid conditions, not using type 3 devices for PAP
(Am J Respir Crit Care Med) titrations or split-night studies, and symptomatic patients who have a negative type
PM Practice Parameters (Sleep)24 3 study should have a PSG.
Type 2, type 4 studies not recommended.
2004 CMS Decision Insufficient evidence to recommend unattended type 2, 3, 4 PM.
2005 AASM Practice Parameters Attended cardiorespiratory study (type 3) is an acceptable alternative to PSG if:
for PSG and Related Procedures2 High pretest probability of OSA.
A negative type 3 study with patients with high pretest probability of OSA is
followed by a PSG.
Here, type 3 is defined as airflow, effort, oximetry, and ECG or heart rate.
Attended cardiopulmonary study acceptable:
Preoperative for planned surgery for snoring or OSA.
After surgery for OSAmoderate to severe.
To document effectiveness of an OA.
After surgical or dental treatment of OSA and symptoms return.
Attended cardiorespiratory study NOT recommended for PAP titration.
AASM Portable Monitoring Task Clinical Guidelines for Unattended Monitoring 20076
Force 20062007
CMS 240.4 Final decision Unattended HST permitted
200820099,10 Type 3 (four channels with ventilation, oximetry, ECG or heart rate, and SpO2).
Type 4 (three channels, one airflow)
PAT type: three channels including PAT, actigraphy, SpO2.
Local Carrier Determinations Restrictions on who can perform and interpret HST.
May require monitoring of airflow.
Set Fee schedule.
Most have followed AASM Clinical Guidelines for unattended monitoring.
AASM = American Academy of Sleep Medicine; ACCP = American College of Chest Physicians; ATS = American Thoracic Society; CMS = Centers for Medicare Services;
ECG = electrocardiogram; HST = home sleep testing; OA = oral appliance; OSA = obstructive sleep apnea; PAP = positive airway pressure; PAT = peripheral arterial
tonometry; PM = portable monitoring; PSG = polysomnography; SpO2 = pulse oximetry.

TABLE 1310
proportions of REM and supine sleep are a significant source
Reasons for Difference in Apnea-Hypopnea Index of night-to-night variability. A study by Smith and associ-
by Polysomnography versus Portable Monitoring ates25 found that patients tend to sleep more in the supine
PM AHI > PSG AHI PSG AHI > PM AHI position in the sleep center. During this study, PSG and PM
Respiratory events Monitoring time > TST (i.e.,
were simultaneously recorded in the sleep center and PM
scored when patient 10/5 < 10/2). was also performed on a separate night at home (Table 13
actually awake. Less supine time at home. 12). Differences in the AHI during simultaneous monitoring
Ethanol intake? PM sensors dislodged were likely due to the effect of using monitoring time versus
More sleep/more REM during the night. TST to compute the AHI. During PM monitoring at home,
sleep at home. Different sensors. less supine sleep also contributed to differences in the AHI.
Night-to-night variability. Different scoring (hypopnea To compensate for night-to-night variability, many PM
Variability in human with arousals only with PSG). devices now have the ability to monitor multiple nights. One
scoring. Night-to-night variability. study suggested that night-to-night variability in the home
Variability in human scoring. might be less than in the sleep center (Fig. 132).26
AHI = apnea-hypopnea index; PM = portable monitoring; PSG = A Bland-Altman plot27 is a commonly used method
polysomnography; REM = rapid eye movement; TST = total sleep time.
to display agreement between two measuring devices. The
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 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 197

TABLE 1311
Effects of Different Proportions of Supine and Rapid Eye Movement Sleep on the Total
Apnea-Hypopnea Index
SUPINE NONSUPINE SUPINE NONSUPINE
NREM NREM REM REM
Assumed AHI (#/hr) in different conditions 5 2 30 10
PROPORTIONS OF DIFFERENT CONDITIONS OVERALL SUPINE NONSUPINE SUPINE NONSUPINE
OF FOUR NIGHTS AND THE RESULTING AHI AHI NREM (%TST) NREM (%TST) REM (%TST) REM (%TST)
Night 1 6.8 40 40 10 10
Night 2 4.2 20 60 0 20
Night 3 3.3 30 65 0 5
Night 4 9.7 70 10 20 0
Note: The AHI was highest on night 4 because the amount of supine REM sleep (as %TST) was the highest on that night.
AHI = apnea-hypopnea index; NREM = nonrapid eye movement; REM = rapid eye movement; TST = total sleep time.

TABLE 1312 Clinical Use of PM

Illustration of the Importance of Less Supine Sleep
Indications for Attended PM
at Home
PM is rarely used in the attended setting. The indications for
PM IN PM as stated in various practice parameters is shown in
LABORATORY UNATTENDED Table 139. In 1994 and 1997 practice parameters,2,20
PSG DURING PSG PM AT HOME attended type 2 or 3 PMs were stated to be acceptable alter-
AHI (#/hr) 25.7 12.2 19.5 16 13.7 13 natives when treatment of OSA is urgent and PSG is delayed,
the patient is unable to be studied in the sleep center (safety
Based on Based on Based on
TST monitoring monitoring or immobility), or the diagnosis of OSA is already estab-
4.0 1.6 hr time time lished and the purpose is to evaluate the response to treat-
7.3 0.8 hr 8.2 0.8 hr ment.1 The 2003 practice parameters for the use of portable
% supine 49 26
monitoring added that certain PMs may be used in the
time attended setting to rule in or to rule out OSA.7 The 2005
median practice parameters for PSG stated that attended cardiore-
spiratory studies (type 3 PM) are an acceptable alternative to
AHI supine 22 19 24 21
PSG for diagnosis of OSA in patients with a high probability
PSG by Embla, PM = Embletta (nasal pressure, chest and abdominal belts,
SpO2, actigraph). of OSA as long as a negative PM study was followed by PSG.
Values shown as mean SD. Attended cardiorespiratory studies were also said to be
Note: Computation of AHI based on a mean of 4 hours with PSG and 7.3 acceptable for preoperative evaluation for planned surgery
hours with PM in the sleep laboratory.
Note: At home, much less supine time was recorded. for snoring or OSA. After surgery, attended cardiorespira-
AHI = apnea-hypopnea index; PM = portable monitoring; tory studies were acceptable to document surgical effective-
PSG = polysomnography; SpO2 = pulse oximetry; TST = total sleep time. ness in patients with moderate to severe OSA. A specific
From Smith LA, Chong DW, Vennelle M, et al: Diagnosis of sleep-disordered
breathing in patients with chronic heart failure: evaluation of a portable statement concerning the use of attended cardiorespiratory
limited sleep study system. J Sleep Res 2007;16:428435. studies in patients being considered for an OA treatment of
snoring or suspected sleep apnea was not made in any of the
practice parameters. The practice parameters for OAs did
state that the presence or absence of OSA must be deter-
difference in paired values (measurement device 1 mea- mined before initiating treatment with oral appliances to
surement device 2) is plotted on the y axis and the average identify those patients at risk due to complications of sleep
of the pair of values (device 1, device 2) is plotted on the x apnea and to provide a baseline to establish the effectiveness
axis. Santos-Silva and coworkers28 compared AHI values of subsequent treatment.6
determined by a type 3 device (Stardust by Philips- If a high probability of OSA is present, an attended car-
Respironics) at home with those determined by PSG. A diorespiratory study would be acceptable based on the 2005
Bland-Altman plot of the data is illustrated in Figure 133. practice parameters.2 In the attended setting, cardiorespira-
In this study, diagnostic agreement between AHI values was tory studies are acceptable to document the effectiveness of
83% (defined as either both AHI values > 30/hr or AHI an OA (after adequate adjustment) or in OSA patients treated
values differing by < 10/hr). with surgery or an OA when symptoms return.
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198 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy

90 90
r  0.56, P  .001 r  0.65, P  .0001
80 80
70 70
PSG overall AHI - retest

PSG

PM overall AHI - retest

PM
60 60
50 50
40 40
30 30
20 20
10 10
0 0
0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70
PSG overall AHI - test PM overall AHI - test
A B
FIGURE 132 A, The apnea-hypopnea index (AHI) on nights 1 and 2 (test vs. retest) in the sleep center with polysomnography (PSG). B, The AHI on nights 1 and 2 (test vs. retest)
at home with portable monitoring (PM). There was less difference between the two nights with PM compared with PSG. Note the considerable night-to-night variability using both
PSG and PM. From Levendowski D, Steward D, Woodson BT, et al: The impact of obstructive sleep apnea variability measured in-lab versus in-home on sample size calculations. Int Arch
Med 2009;2:18.

60

50

40

30
AHI PSG - AHI PM

1.96 SD
20
22.6

10

Mean
0
0.7
10

20 1.96 SD

24.0
30

0 20 40 60 80 100 120 140

Average of AHI PSG in lab versus AHI PM at home

FIGURE 133 A Bland-Altman plot of pairs of apnea-hypopnea index (AHI) values (device 1, device 2). The difference (AHI PSG AHI PM) is
plotted on the y axis against the average on the x axis [(device 1 + device 2)/2]. The confidence limits are + 1.96 standard deviations (SDs). The
mean difference (bias) is near zero. There tended to be more scatter at the higher AHI values. PM = portable monitoring; PSG = polysomnography.
From Santos-Silva R, Truksians V, Truksina E, et al: Validation of a portable monitoring system for the diagnosis of obstructive sleep apnea syndrome.
Sleep 2009;32;629636.

Indications for Unattended PM interpretation are followed8 (Table 1313). In brief, PM

PM is most often used in the unattended setting. The recent must be combined with a comprehensive sleep evaluation by
AASM PMGs8 (see Appendix 132) state that unattended a qualified physician, patients must have a high probability
PM may be indicated for diagnosis of OSA in patients of moderate to severe OSA, there must be an absence of
with a high pretest probability or for documenting the effi- medical co-morbid conditions that degrade the accuracy of
cacy of non-PAP treatments for OSAIF guidelines for PM (severe lung disease, neuromuscular disease, and
patient selection and procedures for PM performance and congestive heart failure). Patients with co-morbid sleep
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 Chapter 13
TABLE 1313
Indications for Use of Unattended
Portable Monitoring
PM must be combined with a comprehensive sleep
evaluation.
Patient has a high pretest probability of moderate to
severe OSA.
No co-morbid medical conditions that may degrade PM
accuracy
Severe pulmonary disease.
Neuromuscular disease.
Congestive heart failure.
No clinical suspicion of other sleep disorders
CSA.
Narcolepsy.
PLMD.
Parasomnias.
Circadian rhythm sleep disorders.
Not for screening asymptomatic populations.
Patients who cannot have PSG due to immobility, safety,
or critical illness.
Unattended PM may be used to monitor response to
non-PAP treatments for sleep apnea (oral appliances,
surgery, weight loss).
Unattended PM in patients home is permitted when all
guidelines are followed.
CSA = central sleep apnea; OSA = obstructive sleep apnea; PAP = positive
airway pressure; PLMD = periodic limb movement disorder; PM = portable
monitoring; PSG = polysomnography.
disorders (e.g., narcolepsy) requiring PSG should also be
excluded. A minimum of airflow, respiratory effort, and
oxygen saturation must be measured (type 3 PM). The same
sensors and respiratory definitions recommended for PSG in
the AASM scoring manual should be used if possible. The
raw data must be reviewed and the PSG interpreted by a
qualified sleep physician. A follow-up visit with the patient
to discuss results is indicated. If a PM study is negative or
technically inadequate, a PSG should be ordered to avoid a
false-negative PM result. The following sections discuss rec-
ommended patient selection and methodology for PM.
Patient Selection for PM
Ideally, each patient should be seen by a BC/BE sleep physi-
cian before PM testing. If this is not possible, an evaluation
can be performed with questionnaires before or at the time
of testing. Review of the medical record to exclude patients
with co-morbidities that degrade PM accuracy is also impor-
tant. In the PMGs, these include patients with severe pulmo-
nary disease, neuromuscular disease, or congestive heart
failure (CHF). The rationale is that such patients may exhibit
hypoventilation without discrete respiratory events or
Cheyne-Stokes breathing (common in severe systolic CHF).
However, one can argue that if PM devices use the same
Polysomnography, Portable Monitoring, and Actigraphy 199
sensors that are used for PSG (the recommendation), then
PM and PSG should have similar ability to detect central
apnea, Cheyne-Stokes breathing, or hypoventilation (mani-
fested by a low SaO2 without discrete events).29 The counter-
argument is that such patients will likely need a PSG PAP
titration. In this case, a split-sleep study may be more cost
effective than PM followed by a PSG titration. PM also would
miss arrhythmias because pulse rate obtained from the
oximeter rather than an ECG tracing is usually recorded. The
AASM PMGs state that PM may be used in the unattended
setting and can be used to document the effectiveness of
non-PAP treatment IF PM guidelines are followed. Examples
would include a study with the patient wearing an OA (after
suitable adjustment) or after previous upper airway surgery.
Recommended PM Methodology
The PMGs8 recommend monitoring at a minimum airflow,
respiratory effort, and SaO2 (Table 1314). The recom-
mended sensors for PM are the same as those recommended
for PSG in the AASM scoring manual.29 Note that CMS uses
the metric RDI rather than AHI for PM [(apneas + hypop-
neas)/monitoring time]. RDI usually means AHI + RERA
index. Adequately trained personnel should either place the
monitoring equipment on the patient or train them on the
application of the sensors. This is essential to avoid a high
percentage of technically inadequate studies. The PM data
must be viewed in the raw form, and if automated scoring is
used, it must be edited for accuracy. A physician must look
at the raw data as well as the data summary before making
an interpretation. It was recommended that PSG be inter-
preted by a BC/BE sleep physician or a physician associated
with an accredited sleep center.
For quality assurance, standard operating procedures for
the PM process must exist. To verify adequate scoring, inter-
rater reliability on scoring of PM studies should be per-
formed on a routine basis and documented. If PM is
inadequate technically or if the study results are negative in
a patient with a high pretest probability of having OSA, an
attended PSG should be performed. The reader may wish to
review the AASM accreditation standards for OOC sleep
testing on the website (www.aasmnet.org).
Types of PM Devices
Numerous devices are available for PM (Fig. 134). Devices
having more sensors provide more information but are more
difficult for patients to place. It is always a trade off between
information and complexity of sensor application. Tracings
from a typical PM device (type 3) are shown in Figures 135
and 136. Figure 135 shows a tracing from a device that
monitors airflow using both an oronasal thermal device and
nasal pressure. Respiratory effort is monitored by chest and
abdominal respiratory inductance plethysmography (RIP)
bands. An oximetry channel and derived heart rate are also
recorded as well as body position. Figure 136 shows a
tracing from a different PM device that monitors airflow by
nasal pressure (with or without oronasal thermistor) and
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200 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy

TABLE 1314
Recommended Portable Monitoring Methodology
Parameters to be monitored Monitor at least three parameters: airflow, effort, and oximetry.
Sensors Same sensors as for PSG
Airflow (ideally two sensors)
Apneaoronasal thermal device.
Hypopneanasal pressure.
Respiratory effortRIP
Pulse oximetry with adequate averaging time and motion artifact rejection.
Personnel and setting PM should be performed by AASM accredited sleep center
Policy and procedures.
Quality assurance program.
Interscorer reliability program.
Experienced sleep technician/technologist either places sensor or directly educates the
patient on sensor application.
Device Display of raw data is available for manual scoring and editing.
Scoring criteria according to AASM scoring manual.
PSG should be performed when PM is technically inadequate or fails to establish diagnosis
of OSA in patients with high pretest probability.
BC/BE SP or physician on Review of raw data by BC/BE SP and interpretation.
staff of AASM accredited
sleep center
Follow-up If PM study is technically inadequate or fails to establish a diagnosis of OSA in a patient
with a high pretest probability, a diagnostic PSG should be performed.
Follow-up visit with MD or trained health care provider after PM testing to discuss results of
test with the patient and plan treatment.
AASM = American Academy of Sleep Medicine; BC/BE SP = Board-certified/Board-eligible sleep physician; OSA = obstructive sleep apnea; PM = portable monitoring;
PSG = polysomnography; RIP = respiratory inductance plethysmography.

A B C D
FIGURE 134 PM devices. A, Embletta (Embla). B, WatchPAT 100 (Itamar). C, Stardust II (Philips-Respironics). D, ARES (Advanced Brain Monitoring).

effort by two RIP belts. The device also records SaO2, body
position by a position sensor in the device, and actigraphy
to enable elimination of periods of wake/artifact from the
final index time (the monitoring time used for AHI calcula-
tion). One useful feature is that the device provides XFlow,
which is an estimate of total flow derived by differentiating
the sum of the chest and abdominal RIP bands. If the airflow
sensors fail (become dislodged), the XFlow signal provides
a backup (Fig. 137). The downside is that the two RIP bands
are more difficult to place than a single effort band. Dispos-
able band material is available for the RIP bands.
Peripheral Arterial Tonometry
Unique PM devices that detect respiratory events by record-
ing changes in sympathetic tone (rather than airflow) using
peripheral arterial tonometry (PAT) are also available.30,31
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 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 201

40
20
N Press Flw Pres 0
20
40
60
24
16
NO flow Flw Ther 8
0
8
16

2
Chest Tho 0
2

3
Abdomen Abd
2
1
0
1
2
80
40
Snore Snore 0
40
80
98
94
95 97 98 98 97 97 96 94
90
91 94 92 92 92 93
SpO2 SpO2 86
87 86 86 88 87
82
78 86
130
90
Pulse Puls Rate 50
10 74 73 65 64 66 66 66 66 66 67 67 68 68 70 72 73 69 66 65 65
30
S S S S S S S S S S S S S S S S S S S S S S S S S S S SS S S S S S S S S S S S S S S S S S S S S S S S S S S S S SS S
Body Pos
Body position
210 211 211 212
10 20 30 40 50 60
1 min.

FIGURE 135 A 60-second tracing shows an obstructive hypopnea recorded with a type 3 PM device (PDX by Philips-Respironics). An oronasal thermal device (NO flow)
and nasal pressure (N Press), chest and abdominal respiratory inductance plethysmography (RIP) bands, snoring, oximetry, pulse rate (from the oximeter), and body position
(S = supine) are recorded. SpO2 = pulse oximetry.

Devices using this technology (WatchPAT 100, 200, Itamar

Medical) are worn on the wrist. The devices have two
probesa PAT probe and an oximetry probeworn on sepa-
rate digits. The PAT signal is a measure of the blood volume
in the digit. Increases in sympathetic tone stimulate alpha
receptors on the digital blood vessels, causing constriction. A
reduction in blood flow to the digits decreases the finger tip
volume and the PAT signal. Because surges in sympathetic
tone follow respiratory event termination, the combination of
a decrease in PAT signal, a fall in pulse oximetry (SpO2) fol-
lowed by an increase, and an increase in heart rate allows
determination of respiratory events (Fig. 138). Nonrespira-
tory arousals would not reduce the SpO2. The device has a
built-in actigraphy to help with estimation of an appropriate
index time (used to compute an event index). Recently, the
combination of actigraphy and the PAT signal has been used
to determine estimates of wake, nonrapid eye movement
(NREM) sleep, and REM sleep because the sympathetic tone
characteristics of these sleep stages differ. Newer models also
have a body position sensor and a snore sensor. The device has
been validated with several studies. The device cannot be used
in patients on alpha blockers (e.g., terazosin) and with patients
in atrial fibrillation. Another downside is that the PAT probes
are relatively expensive. The national carrier determination
for HST recognizes 3 channels of monitoring including PAT,
oximetry, and actigraphy as a valid PM method. However,
not all LCDs will allow reimbursement for PAT studies. The
device does not fall within recommended PMGs. Recently,
the ability to edit events in the program analyzing the infor-
mation has been improved. New 2011 procedure codes for
PM devices now include PAT devices (see Table 138).
Practical Considerations in PM
A systematic approach is indicated to avoid a high percent-
age of technically inadequate PM studies. The choice of the
device (Table 1315) and method of device application
(Table 1316) are major considerations. Devices with more
sensors provide more information but are more difficult
to apply. The software should provide accurate autoscoring
to minimize the amount of event editing required. If the
software is similar to that used for PSG, this may be an
advantage to reduce training costs. The durability of the
device and cost of expendables (e.g., nasal cannula) should
be considered.
PM devices can be placed in the sleep center or in the
home by a technologist (see Table 1316). Alternatively, the
patient can be trained on the device and apply the device
himself or herself at home. PM devices are typically either
returned to the sleep center the following day or mailed if
patients live a distance from the center. Device loss can be a
major expense. The application of the PM device by a tech-
nologist in private homes is expensive and has safety issues.
Therefore, having patients come to the sleep center is recom-
mended if possible. The more complex the PM device, the
less likely patients can apply it themselves. Adequate training
is essential. One option is to have patients practice in the
sleep center, and if they are unable to successfully attach the
device, they can simply wear the device home. It is also pos-
sible to give patients the option of wearing the device home
or applying it themselves. In a study by Golpe and col-
leagues,32 setup of PM device in the patients home resulted
in 7% of inadequate studies whereas having the patients
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202 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy

Nasal flow
Apnea central (12.90s) Apnea central (15.20s)
200

100

Nasal pressure 0
(flow)
100

200

mL/s
Thermistor
3

Oronasal thermal 2

1
device
0

1

2

3
mV
Resp.Mo...

RIP thorax Thorax

RIP abdomen Abdomen

192V/cm
Desaturation (21.33s) [8] Desaturation (18.33s) [7]

98
98
98
97
97

97
97
97
96
96
98

96
96

96

96
96
96
98
98
97
97
97
95
95
95

95

95
95
100
94

94

94
94

94
94
93
93

93
92

92

92

92
SpO2 - %

91

91
91
91
SpO2
90

90

90
89
89

90

80

70

60
175

150

125
Pulse - bpm

100

Pulse
66
65
62

60
60
59
61
61
61

60

58
58
59
59
57
59
57

75

58

55
55

55
55
55

55

55
52
53
53
57

53
54
54

54
54

53

51
53
53

54
53

51
53
51
49
50
51

49
49

49
49
50

25

FIGURE 136 Tracing from a type 3 PM device (Embletta by Embla) shows nasal pressure, oronasal thermal flow, chest and abdominal respiratory inductance plethysmography
(RIP) channels, oximetry (SpO2), and pulse. Body position and actigraphy were also recorded but are not shown. The illustrated event is a central apnea of the Cheyne-Stokes
type. This was an unexpected finding. The patient had no history of known congestive heart failure but did report nocturnal dyspnea.

apply the devices themselves had 33% inadequate studies.
This study used a five-channel device recording oronasal
airflow, wrist actigraphy, body position, and SaO2. In our
experience, patients have difficulty applying some types of
oximeter probes as well as chest and abdominal belts. Other
common problems include dislodgment of either the nasal
cannula or the oximeter probe as well as pulling leads out of
the PM device during body movement. Patients can be
trained to apply tape at strategic points to reduce these
events. The selection of the device to be used must take into
account how the setup will be delivered.
It is also useful to have patients complete a brief sleep
diary to record their estimate of how long they slept and if
the night of sleep was fairly typical. An occasional patient
will sleep very poorly with the device attached. If minimal
sleep is recorded, a false-negative study is likely. Devices
that can record more than one night provide another moni-
toring night opportunity and may also reduce the influence
of night-to-night variability.
Integration of PM into the Overall Patient
Care Algorithm
Diagnosis of OSA using PM is only the first part of the process
if the study is positive. It is expected that in populations with
a high probability of OSA, a high percentage of PM tests will
be positive. If PAP is chosen for treatment, there are several
alternative pathways to proceed (Table 1317).3335 The stan-
dard approach would be to perform a PSG PAP titration and
subsequent PAP treatment. Patients could also use an auto-
PAP (autotitrating, autoadjusting, positive airway pressure
[APAP]) device at home for 3 days or more and information
obtained could be used to select a pressure for chronic CPAP
treatment.33,35 APAP devices automatically provide the lowest
effective pressure during the night. Commonly, the 90th or
95th percentile pressure is chosen for treatment with a fixed
pressure (CPAP). The use of APAP devices is discussed in
Chapter 19. A third possible approach is starting CPAP at a
pressure derived using prediction equations with subsequent
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 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 203

Nasal flow (219mL/s/cm)

Nasal flow

XFlow

XFlow (335V/s/cm)
Thorax (221V/cm)

Thorax

Abdomen (146V/cm)

Abdomen

SpO2 (15.9%/cm)

94%
SpO2
80%

FIGURE 137 In this tracing from an Embletta, the nasal flow channel is inadequate (likely nasal cannula dislodged or occluded) but the derived XFlow
(derivative of thorax and abdomen RIP bands) provides a reasonable estimate of flow. SpO2 = pulse oximetry.

adjustment based on oximetry, symptoms, or machine esti-

mates of residual AHI.13,3335 Finally, simply treating the
patient with an auto-PAP (autoadjusting) eliminates the
need for titration. These approaches are discussed in Chapter
19 (PAP treatment). If a high percentage of PM studies are
positive, a reasonable question to consider is the relative cost-
benefit of algorithms using PM for diagnosis compared with
one using split PSG. Issues of cost and reimbursement will
vary between settings (VA Health Care System vs. private
sector). If a large number of PM studies need to be repeated
or validated by a PSG to eliminate false negatives, any cost
savings from using PM will be reduced. Currently, in the
United States, unattended autotitration is not reimbursed. In
addition, whereas APAP devices cost DME companies more,
insurance carriers reimburse them at the CPAP level. These
conditions limit the application of alternative diagnostic
treatment pathways to special settings such as the VA Health
Care System. The very modest reimbursement for PM studies
also discourages routine use of these studies.
Overall Approach to Using PSG and PM
An overall approach to using a combination of PSG and PM
is presented in Figure 139.
Economic factors at present limit this approach but wider
use may be practical in the future. A clinical evaluation
determines whether there is a high probability of OSA, if
other sleep disorders are present, or whether complicating
issues are present that will likely require a PSG titration.
Patients with a high probability of OSA undergo PM, and if
OSA is diagnosed, they can have APAP treatment or APAP
titration followed by CPAP treatment. If the PM is negative,
a PSG can be performed. If other sleep disorders are sus-
pected or there are complicating factors such as CHF
(Cheyne-Stokes possible), narcotics, obesity hypoventilation
possible (supplemental oxygen or massive obesity), a PSG
with split study if indicated is performed. Although PM can
often diagnose Cheyne-Stokes breathing, a PSG titration will
likely be needed.
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204 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy

1080 Resp. Event Resp. Event Resp. Event

795
530
265
0
PAT PAT 265
530
795
1080
1325
1880
1705
1550
PAT 1395
PAT amplitude amplitude 1240
1085
930
775
620
78 Increased
72 sympathetic
68 tone
PulseRate 64
Pulse (BPM)
60
56
100 Desaturation Desaturation De
98
96
94
92
SaO2 90
SaO2 (%) 88
86
84
82
80
Resp event

FIGURE 138 Peripheral arterial tonometry (PAT) detection of a respiratory event. The PAT signal falls (increased sympathetic tone) associated with an increase then a
decrease in pulse and an arterial oxygen desaturation. SaO2 = arterial oxygen saturation.

TABLE 1316
TABLE 1315 Method of Device Setup and Return
Practical Considerations in Portable Monitoring
SLEEP CENTER SETUP
Choice of Device
Advantages
More complex PM devices provide backup sensors and
Controlled environment
more informationbut are more difficult to place.
Technologist can place device
Multiple-night recording ability may reduce night-to-night
Disadvantages
variability effects.
Travel cost for patients (two round trips unless device
An automatic scoring program that is accurate and easily mailed back)
editable is essential given low reimbursement for IN-HOME SETUP
technical component.
Technologist Travels to Home
Ease of device setup is essentialif patient is to self-apply
device. Advantages
Lower % technically inadequate studies (compared with
Efficient device use requires ability to patient sensors at home)
Clean device and reprogram easily.
Rapid device turnaround requires a systematic Disadvantages
approach. Travel costs
Technologist safety issues
Methods of dealing with device damage or loss
Mail Device to Patient
Patient signing responsibility contract.
Warranty options. Requires simple device
PM = portable monitoring. Higher percentage of failed studies
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 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy 205

TABLE 1317
Positive Airway Pressure Treatment after Portable
Monitoring Diagnosis of Obstructive Sleep Apnea
PSG PAP titration followed by CPAP treatment
Autotitration followed by CPAP treatment
CPAP on empirically determined pressure
Adjustment on basis of residual snoring/apnea
Adjustment on basis of bed partner observations
Adjustment based on pulse oximetry
Adjustment based on device estimate of residual AHI
Treatment with APAP device
APAP = autotitrating, autoadjusting positive airway pressure;
AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure;
PAP = positive airway pressure; PSG = polysomnography (see Chapter 19).
ACTIGRAPHY
Actigraphy utilizes a portable device (the actigraph) usually
worn on the wrist that records movement over an extended
period of time (Fig. 1310). Sleep-wake patterns are esti-
mated from the pattern of movement. Software is available
to estimate TST and wake time from the data. The estimates
of TST and wake time are more accurate in normal individu-
als than in patients with sleep disorders. However, the sleep-
wake pattern of actigraph data is extremely valuable in
documenting patterns of sleep and wake. AASM practice
parameters have been published in 2005 and most recently
in 2007.36,37 The temporary Healthcare Common Procedure
Coding System (HCPCS) code for actigraphy was 0089T. In
2009, actigraphy received a current procedural terminology
(CPT) code. The new code is 95803actigraphy testing,
recording, analysis, interpretation, and report (minimum of
72 hr14 consecutive days of recording). Medical practices
often set fees for actigraphy in the $250 to $300 range.

Clinical
evaluation

OSA likely and uncomplicated Other sleep Complications OSA less likely
Disorders suspected Very high BMI
Narcolepsy, PLMD, (likely to need high PAP)
RBD OHS
Mod-severe COPD
PM Neuromusc Ds
On 24 hour oxygen
Potent narcotics
CHF (if CSB, may need ASV)
Clinic
No

AHI  5/hr AHI  5hr Narcolepsy

CSB or frequent AHI  5hr PSG
No CSA suspected?
CSA AHI
 5/hr
Yes
AHI  5/hr
MSLT
APAP APAP Split
treatment titration study
PAP PSG
titration

CPAP
treatment PAP
treatment

FIGURE 139 Systematic approach to using combination of polysomnography (PSG) and portable monitoring (PM) to evaluate patients. AHI = apnea-hypopnea index; APAP =
autoadjusting, autotitrating positive airway pressure; ASV = adaptive servo-ventilation, a treatment for CSA or CSB; BMI = body mass index; CHF = congestive heart failure; COPD =
chronic obstructive pulmonary disease; CPAP = continuous positive airway pressure; CSA = central sleep apnea; CSB = Cheyne-Stokes breathing; MSLT = multiple sleep latency test;
DaneshGroup.com
OSA = obstructive sleep apnea; PAP = positive airway pressure; PLMD = periodic limb movement disorder; RBD = rapid eye movement sleep behavior disorder.
206 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy

Actogram:
12:00 PM 8:00 PM 12:00 AM 6:00 AM 12:00 PM

Friday
9/4/2009
(Day 1)

Saturday
9/5/2009
(Day 2)

Sunday
9/6/2009
(Day 3)

Monday
9/7/2009
(Day 4)

Tuesday
9/8/2009
(Day 5)

Wednesday
9/9/2009
(Day 6)

Thursday
9/10/2009
(Day 7)

12:00 PM 8:00 PM 12:00 AM 6:00 AM 12:00 PM

FIGURE 1310 Actigraphy. The dark black represents the amount of activity (when present = wake). The light blue represents periods of low activity identified as sleep.
The light gray represents ambient light detection. This patient had irregular bedtimes.

However, at this writing, actigraphy is still not reimbursed
by most insurance plans or Medicare. Studies of actigraphy
have usually compared the results with that of PSG or sleep
logs. However, actigraphy does not measure sleep (EEG) or
the subjective experience of sleep (sleep logs).
Indications
The indications for actigraphy are listed in Table 1318.
Actigraphy provides a fairly accurate estimate of sleep pat-
terns in normal, healthy adult populations and in patients
suspected of certain sleep disorders. Actigraphy is indicated
to assist in the evaluation of patients with advanced sleep
phase syndrome (ASPS), delayed sleep phase syndrome
(DSPS), and shift work disorder. In addition, there is some
evidence to support the use of actigraphy in the evaluation
of patients suspected of jet lag disorder and non24-hour
sleep-wake syndrome (including that associated with blind-
ness). Actigraphy is also useful for documenting the response
to treatment in circadian disorders.
When PSG is not available, actigraphy is indicated to
estimate TST in patients with OSA.37 In patients with insom-
nia and hypersomnia, there is evidence to support the use
of actigraphy in the characterization of circadian rhythms
and sleep patterns/disturbances. In assessing response to
therapy, actigraphy has proved useful as an outcome measure
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 Chapter 13
TABLE 1318
Indications for Actigraphy
1. Assess the sleep-wake patterns of normal individuals.
(Standard)
2. To assist in evaluation of suspected circadian rhythm
sleep disorders.
Advanced sleep phaseIndicated. (Guideline)
Delayed sleep phaseIndicated. (Guideline)
Shift work disorderIndicated. (Option)
Free-running circadian rhythm sleep disorder (non-
24 hr)Indicated. (Option)
ISWRIndicated. (Option)
Jet lag disorderNot indicated for diagnosis.
(Guideline)
3. When PSG is not available, actigraphy provides an
estimate of total sleep time in OSA. When used with
respiratory monitoring, actigraphy may improve the
accuracy in assessing severity (AHI). (Standard)
4. Actigraphy is indicated to characterize circadian rhythm
patterns or sleep disturbance in individuals with
insomnia, including insomnia with depression. (Option)
5. Actigraphy is indicated to determine circadian pattern
and estimate average daily sleep time in individuals
complaining of hypersomnia. (Option)
6. Actigraphy is useful in assessing response to therapy in
Circadian rhythm sleep disorders.
Insomnia.
7. Actigraphy is useful
A. Characterizing sleep and circadian rhythm patterns as
well as treatment outcomes among older individuals
living in the community, especially if used in
conjunction with other measures such as sleep
diaries/caregiver observations.
B. Characterizing sleep and circadian rhythm patterns
and documenting treatment outcome in older
nursing home residents.
C. Delineating sleep patterns and documenting
treatment responses in normal infants and children
and in special pediatric populations (PSG difficult
and difficult to interpret).
AHI = apnea-hypopnea index; ISWR = irregular sleep wake rhythm;
OSA = obstructive sleep apnea; PSG = polysomnography.
in patients with circadian rhythm disorders and insomnia.
In older adults (community dwelling and nursing home resi-
dents), sleep monitoring can be difficult. Actigraphy is indi-
cated for characterizing sleep and circadian patterns and to
document treatment responses. Similarly, in normal infants
and children, as well as special pediatric populations, actig-
raphy has proved useful for delineating sleep patterns and
documenting treatment responses.
Actigraphy in OSA
If the number of events detected by PM was divided by a
better estimate of TST than the monitoring time, this might
improve the estimate of the AHI. However, patients with
OSA by the very nature of the disorder have periodic
Polysomnography, Portable Monitoring, and Actigraphy 207
movements at the end of respiratory events. Hedner and
associates38 validated a special actigraphic system optimized
for use in OSA patients. The device was compared with PSG
on an epoch-by-epoch basis. The overall sensitivity and
specificity to identify sleep were 89% and 69%, respectively.
The agreement ranged from 86% in the normal subjects to
86%, 84%, and 80% in the patients with mild, moderate, and
severe OSA, respectively. There was a tight agreement
between the mean values of actigraphy and PSG in deter-
mining mean sleep efficiency, TST, and sleep latency. Whereas
for most individuals, the difference between the PSG and the
actigraphy was relatively small, for some, there was a sub-
stantial disagreement. Another study did not find good
agreement between actigraphic and PSG estimates of TST.39
Elbaz and coworkers40 used actigraphy combined with
respiratory monitoring and found a better estimate of the
AHI than use of time in bed. The utility of actigraphy with
PM remains to be determined. However, it certainly allows
elimination of large portions of the night in which wake is
obvious.
Patients with Hypersomnia
Practice parameters on use of PSG/MSLT to diagnose nar-
colepsy stated that sleep logs may be obtained for 1 week
before to assess sleep-wake schedules. Not all patients can
keep accurate sleep logs. Therefore, actigraphy could be
potentially useful to document sleep patterns before MSLT.
However, current practice parameters for actigraphy37 do not
list evaluation of sleep before MSLT as an indication.
Actigraphy in Insomnia
The practice parameters for actigraphy did not recommend
testing as a routine evaluation of patients with insomnia.
However, actigraphy was said to be useful in documenting
sleep-wake patterns.37 Therefore, documenting sleep pat-
terns rather than the absolute amount of sleep and wake is
likely the best use of the actigraph. In insomnia patients,
periods of low activity in which patients lay quietly in bed
but are awake may be scored as sleep by actigraphy software.
When performing actigraphy, it is essential to require
patients to complete a sleep log (lights off, lights on, out of
bed, actigraph off for shower, and so on, estimated TST; and
sleep latency). This information enables a correct interpreta-
tion of actigraphic tracings. For example, total absence of
movement usually indicates that the actigraph has been
removed (shower, swimming), but here patient logs are
essential to verify device removal. Many modern wrist acti-
graph devices also provide the capability of recording the
amount of ambient light. This is useful in patients with cir-
cadian rhythm sleep disorders in whom light exposure may
either exacerbate or improve the underlying disorder. Some
actigraphy devices also have event markers that the patient
can press when getting in bed, trying to sleep, or after awak-
ening in the morning.
Sleep logs and actigraphy provides complementary infor-
mation. In a study of patients with insomnia undergoing
treatment, Vallires and Morin41 compared findings from
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208 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy

Log/PSG
Log/PSG
2 2
Act/PSG

1 Act/PSG Log/PSG 1

Act/PSG
Act/PSG

0 0
TST Wake Sleep latency TST Wake Sleep latency

A B
FIGURE 1311 A, A plot of the ratios of actigraphic/polysomnography (Act/PSG) and sleep log/PSG estimates of total sleep time (TST), wake, and sleep latency from the
data of a study by Vallires and Morin in patients with insomnia. Both Act and sleep logs slightly underestimated the TST but overestimated wake time. Sleep logs
overestimated sleep latency and Act underestimated sleep latency (laying in bed still but awake). B, A plot of Act/PSG ratios (all three bars) for TST, wake, and sleep latency
from a study of older insomniacs by Sivertsen and coworkers. Act slightly overestimated TST but underestimated wake and sleep latency. A, Data from Vallires A, Morin
CM: Actigraphy in assessment of insomnia. Sleep 2003;26:902906; B, data from Sivertsen B, Omvki S, Havik OE, et al: A comparison of actigraphy and polysomnography in
older adults: treatment of chronic primary insomnia. Sleep 2006;29:13531358.

actigraphy and sleep logs with PSG (Fig. 1311A). Both
actigraphy and sleep logs underestimated TST and overesti-
mated wake time. Actigraphy underestimated the sleep
latency whereas sleep logs overestimated the sleep latency.
They found actigraphy to be more sensitive at detecting
treatment effects than sleep logs. In contrast, Sivertsen
and coworkers42 found different results in a group of older
adults treated for primary insomnia (expected to have
more wake time). Actigraphy slightly overestimated TST
and underestimated wake (see Fig. 1311B). In this study,
actigraphy provided a better estimate of TST than of wake
time.
2. A 40-year-old man was referred to the sleep center with
a long history of loud snoring, witnessed apnea, and
daytime sleepiness. The physical examination shows a
BMI of 31 kg/m2, and a very long, swollen uvula. His
neck is 18 inches in circumference. The patient is other-
wise healthy. Which of the following would you do next?
A. PM (type 3 airflow, effort, SaO2, heart rate).
B. Attended PSG.
C. Nocturnal oximetry.
D. Treatment with APAP.
E. Refer him for an OA or surgery to treat primary
snoring.

CLINICAL REVIEW QUESTIONS
1. A 45-year-old man referred to the sleep laboratory with
a long history of snoring, witnessed apnea, and daytime
sleepiness. The physical examination shows a body mass
index (BMI) of 31 kg/m2, very crowded upper airway,
and neck circumference of 17 inches. An unattended
PM (type 3) sleep study found an AHI of 3.5 events/hr
with the lowest SaO2 being 89%. The patient reports he
did not sleep that well (worried about pulling out wires
from PM device). Which of the following would you do
next?
A. Repeat PM (type 3).
B. Attended PSG.
C. Tell the patient that he doesnt have OSA.
D. Refer him for an OA or upper airway surgery to treat
primary snoring.
3. A 40-year-old man was referred to the sleep center
with a history of loud snoring that bothers his wife. The
patient denies daytime sleepiness. His wife has never
noted breathing pauses. The patient has been evaluated
by an ear-nose-throat (ENT) physician who recom-
mends upper airway surgery for snoring. On exami-
nation, he has a long uvula but a minimally crowded
upper airway. His neck circumference is 15 inches and
his BMI is 22 kg/m2. Which of the following do you
recommend?
A. Proceed to have the upper airway surgery.
B. Schedule for a PSG.
C. Schedule for oximetry (type 4 PM).
D. Schedule an unattended type 3 PM study.
4. You are asked to follow a 50-year-old woman who was
diagnosed with OSA about 2 years ago at another sleep
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 Chapter 13
center. She was placed on CPAP at 8 H2O. Her initial
symptoms of snoring and daytime sleepiness have
resolved, and she reports using her CPAP nightly. She is
otherwise healthy. There has been no change in her
weight (BMI = 31 kg/m2), her menopause status (post-
menopausal), or medications (for hypertension). Which
of the following do you recommend?
A. Clinical follow-up in 1 year or sooner if symptoms
recur.
B. Verify CPAP compliance objectively from machine
information.
C. Order a PSG on CPAP.
D. Order a diagnostic PSG to see if CPAP is still
needed.
5. A 35-year-old man with OSA had palatal surgery per-
formed 3 months ago for OSA (preoperative AHI was
25/hr). He reports that his snoring is much improved
and that his daytime sleepiness is better as well. Physical
examination shows a well-healed palatal scar. Which of
the following do you recommend?
A. PSG.
B. Nocturnal oximetry.
C. Clinical follow-up only.
D. PSG if symptoms return.
6. A 55-year-old man was recently diagnosed with CHF.
He has been treated with a beta blocker, angiotensin-
converting enzyme inhibitor, and diuretic, but continues
to have nocturnal dyspnea and frequent awakenings. He
reports only mild snoring that is unchanged. On physi-
cal examination, he has minimal upper airway crowding
but has basilar crackles and 1+ pedal edema. Which of
the following do you recommend?
A. Increased diuretic dose.
B. PSG.
C. Trial of a hypnotic to consolidate sleep.
D. Unattended type 3 PM.
7. A 75-year-old man recently had a left-sided cerebrovas-
cular accident and now has mild right hemiparesis. Per
spouse, there is no snoring or witnessed apnea. He com-
plains of insomnia and frequent nocturnal arousals.
Physical examination is notable for the hemiparesis and
moderate obesity. Which of the following do you
recommend?
A. SpO2.
B. PSG.
C. Unattended cardiorespiratory sleep study (level 3).
D. Cognitive behavior therapy for insomnia.
E. Empirical trial of a hypnotic.
8. A 16-year-old boy with Duchennes muscular dystrophy
complains of frequent episodes of nocturnal dyspnea
and frequent awakenings. He is wheelchair-bound and
Polysomnography, Portable Monitoring, and Actigraphy 209
has extreme muscle weakness. Physical examination
shows diffuse muscle atrophy and weakness, obesity.
Arterial blood gases on room air show arterial partial
pressure of oxygen (PaO2) = 65 mm Hg, SaO2 = 92%,
arterial partial pressure of carbon dioxide (PaCO2) =
46 mm Hg. Which of the following do you recommend?
A. Empirical nocturnal low-flow O2.
B. Nocturnal SpO2 arterial oxygen saturation
monitoring.
C. PSG.
D. Hypnotic.
9. A 45-year-old woman has complaints of poor sleep
with frequent nocturnal arousals. Her husband says
that she kicks her legs at night. Only mild snoring
and no witnessed apneas are reported. The patient
DENIES symptoms of the RLS. Which of the following
is recommended?
A. PSG.
B. Unattended type 3 PM study.
C. Sleep diary for 2 weeks.
D. Empirical treatment with a hypnotic.
E. Actigraphy
10. A 60-year-old woman is complaining of severe difficulty
initiating and maintaining sleep. This has not improved
with several hypnotics and cognitive behavioral therapy
for insomnia. Her husband reports mild snoring and no
breathing pauses. She has coronary artery disease and
has recently undergone an angioplasty with two stents.
The patient also has a long history of hypertension and
diabetes mellitus. Her medications include clopidogrel
and aspirin. Physical examination shows moderate
obesity and a slightly crowded oropharynx. Which of
the following do you recommend?
A. Ask the patient whether she snores and/or has
daytime sleepiness.
B. PSG.
C. SpO2.
D. Actigraphy.
E. Cognitive behavioral therapy.
11. A PM test is performed for insomnia and the results are
listed here. The patient reports loud snoring but no
daytime sleepiness. What do you recommend?
Monitoring time: 7 hr.
AHI (based on monitoring time) = 3/hr.
Events: 13 obstructive apneas, 8 hypopneas.
Desaturations: 70, with oxygen desaturation index
(ODI) of 10/hr, lowest SpO2 = 83%.
A. PSG.
B. Evaluate raw tracings.
C. Treatment for snoring.
D. Inform the patient that OSA is not present.
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210 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
Answers
1. B. PM can give false-negative results, especially if the
patient sleeps very poorly. Because there is a high index
of suspicion, a PSG should be ordered. Patients with a
high pretest probability for OSA but a negative PM
study should have a full night PSG.
2. A or B. This patient has a high pretest probability of
having OSA. A PM study is indicated in combination
with a comprehensive sleep evaluation if PM is per-
formed according to AASM PMGs. Of course, ordering
a PSG is also indicated and is the gold standard.
Treatment of snoring by either surgery or an OA should
not be undertaken if OSA is ruled out. Unlike snoring,
a posttreatment PSG or PM is indicated if OSA is
present.
3. B. A PSG (or attended type 3 PM) should be performed
before upper airway surgery for snoring or OSA. If sig-
nificant OSA is present, other treatments might be con-
sidered. The study will also document as baseline (for
comparison with postoperative PSG). Note that the
practice parameter for PSG 2005 does specify that either
a PSG or an attended type 3 (cardiorespiratory) study
be performed. Note that an unattended type 3 study
can be used for non-PAP treatment follow-up. It should
be used as a diagnostic study only if there is a high
probability of OSA. In this case, the patient is not high
probability (no witnessed apnea, no increased neck
circumference).
4. B. Follow-up PSG or an attended cardiorespiratory
(type 3) sleep study is NOT routinely indicated in
patients treated with CPAP whose symptoms continue
to be resolved with CPAP treatment. It is good clinical
practice to objectively document CPAP adherence
(patients often overestimate their use). In the absence of
significant weight loss, there is no reason to believe that
CPAP is no longer needed.
10. B. Patients with coronary artery disease should be eval-
5. A. After upper airway surgery for OSA, a PSG or
attended level 3 study is indicated routinely to assess
treatment results (after surgical healing). AASM PMGs
state that an unattended type 3 PM may be indicated
if performed following AASM guidelines. Improvement
in symptoms is unreliable as is SpO2 monitoring for the
diagnosis of OSA in this setting.
6. B. A large percentage of patients with systolic or dia-
stolic heart failure have some form of SRBD. A PSG is
indicated if they have nocturnal symptoms suggestive of
SRBDs (disturbed sleep, nocturnal dyspnea, snoring) or
if they remain symptomatic despite optimal medical
management of CHF. The current patient reported fre-
quent awakenings and nocturnal dyspnea on treatment.
Of note, many patients with CHF and OSA or CSA do
NOT report daytime sleepiness.
7. B. Patients with history of stroke or TIAs should be
evaluated for symptoms and signs of sleep apnea. If there
is suspicion of sleep apnea, the patients should undergo
a PSG. There is a high incidence of CSA or OSA after
CVA. Given that the symptoms are suspicious (frequent
nocturnal arousals) but do not fall into the high prob-
ability of moderate to severe OSA category, an unat-
tended PM type 3 is not indicated. SpO2 is not sensitive
enough in this situation. Before treating insomnia, OSA
should be ruled out with a PSG.
8. C. According to the AASM practice parameters, for
patients with neuromuscular disorders and sleep-related
symptoms, PSG is routinely indicated to evaluate
symptoms of sleep disorders that are not adequately
diagnosed by obtaining a sleep history, assessing
sleep hygiene, and reviewing sleep diaries. The main
concern here is nocturnal hypoventilation. Noninvasive
PAP ventilation (not supplemental oxygen) is indicated
for nocturnal hypoventilation. In this setting, SpO2
can be useful and some would argue that this is also a
correct answer. However, PSG can determine whether
OSA, nocturnal hypoventilation, or a combination is
present.
9. A. PSG is indicated when a diagnosis of PLMD is
considered because of complaints by the patient or
an observer of repetitive limb movements during sleep
and frequent awakenings, fragmented sleep, difficulty
maintaining sleep, or EDS. A PSG is NOT indicated for
diagnosis of RLS. Of note, some patients with OSA also
have leg kicks at night. A PM study would not be indi-
cated because it does not address the leg movements.
PLMD is thought to be uncommon. In this setting,
actigraphy might be useful if the OSA and PLMD are
ruled out. Empirical treatment with hypnotics is not
recommended until the nature of the disturbance is
identified.
uated for symptoms and signs of sleep apnea. If there is
suspicion of sleep apnea, the patients should undergo a
sleep study. Answer A could also be considered as being
correct. However, whereas snoring and EDS are cardinal
symptoms of OSA, some patients complain of insomnia.
PSG is not routinely indicated for insomnia. However,
in cases that do not respond to treatment, especially
in high-risk settings, a PSG is probably the safest
course. Note that the practice parameters do NOT say
that an unattended type 3 PM study is indicated in this
situation. If the TST is much less than the monitoring
time, PM may also underestimate the AHI. The practice
parameters for using PSG to evaluate insomnia4 state
Polysomnography is indicated when initial diagnosis is
uncertain, treatment fails (behavioral or pharmaco-
logic), or precipitous arousals occur with violent or inju-
rious behavior. (Guideline)
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 Chapter 13
11. B. There is an inconsistency between the ODI of 10/hr
and the AHI of 3/hr. The technical adequacy of the
oximetry and flow tracings should be determined. In
many cases, the ODI is more accurate than the AHI. The
other explanation for the above findings is that the auto-
mated scoring did not pick up respiratory events where
a desaturation is present. Scoring may need to be manu-
ally edited. Whereas a PSG could be indicated, the first
issue is to determine whether the PM study already per-
formed can provide an accurate estimate of breathing
abnormalities.
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32. Golp R, Jimenex A, Carpizo R: Home sleep studies in the
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33. Masa JF, Jimenez A, Duran J, et al: Alternative methods of
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with obstructive sleep apnea titrate their own continuous posi-
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36. Littner MR, Kushida DA, Anderson WM, et al: Standards of
Practice Committee of the American Academy of Sleep Medi-
cine: practice parameters for the role of actigraphy in the study
of sleep and circadian rhythms: an update for 2002. Sleep
2003;26:337341.
37. Morgenthaler T, Alessi C, Friedman L, et al: Practice parame-
ters for the use of actigraphy in the assessment of sleep and
sleep disorders: an update for 2007. Sleep 2007;30:519529.
38. Hedner J, Pillar G, Pittman SD, et al: A novel adaptive wrist
actigraphy algorithm for sleep-wake assessment in sleep apnea
patients. Sleep 2004;27:15601566.
39. Penzel T, Kesper K, Pinnow I, et al: Peripheral arterial tonom-
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41. Vallires A, Morin CM: Actigraphy in assessment of insomnia.
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AASM Practice Parameters for Polysomnography
(Selected Statements)
4.1.3.1 Polysomnography is routinely indicated for the
diagnosis of sleep-related breathing disorders (SRBDs).
(Standard)
4.1.3.2 Polysomnography is indicated for positive
airway pressure (PAP) titration in patients with SRBDs.
(Standard)
4.1.3.3 A preoperative clinical evaluation that includes
polysomnography or an attended cardiorespiratory (type 3)
sleep study is routinely indicated to evaluate for the presence
of obstructive sleep apnea (OSA) in patients before they
undergo upper airway surgery for snoring or OSA.
(Standard)
4.1.3.4 Follow-up polysomnography or an attended car-
diorespiratory (type 3) sleep study is routinely indicated for
the assessment of treatment results in the following circum-
stances: (Standard)
1. After good clinical response to oral appliance treat-
ment in patients with moderate to severe OSA.*
2. After upper airway surgery in patients with moderate
to severe OSA, to ensure therapeutic benefit.
3. After surgical or dental treatment of patients with
SRBDs whose symptoms return despite a good initial
response to treatment.
4.1.3.5 Follow-up polysomnography is routinely indi-
cated for the assessment of treatment results in the following
circumstances: (Standard)
1. After substantial weight loss (e.g., 10% of body weight)
has occurred in patients on continuous positive airway
pressure (CPAP) for treatment of SRBDs to ascertain
whether CPAP is still needed at the previously titrated
pressure.
2. After substantial weight gain (e.g., 10% of body weight)
has occurred in patients previously treated with CPAP
successfully, who are again symptomatic despite the
continued use of CPAP, to ascertain whether pressure
adjustments are needed.
6
*Amended in Practice Parameters for Oral Appliance treatment to
include mild, moderate, and severe OSA.
Appendix 13-1
3. When clinical response is insufficient or when sym-
ptoms return despite a good initial response to treat-
ment with CPAP. In these circumstances, testing
should be devised with consideration that a concur-
rent sleep disorder may be present (e.g., OSA and
narcolepsy).
4.1.3.6 Follow-up polysomnography or a cardiorespira-
tory (type 3) sleep study is NOT routinely indicated in
patients treated with CPAP whose symptoms continue to be
resolved with CPAP treatment. (Option)
4.1.3.7 A multiple sleep latency test is not routinely indi-
cated for most patients with SRBDs. A subjective assessment
of excessive daytime sleepiness should be obtained routinely.
When an objective measure of daytime sleepiness is also
required, previously published practice parameters should
be consulted. (Standard)
4.1.3.8 Patients with systolic or diastolic heart failure
should undergo polysomnography if they have nocturnal
symptoms suggestive of SRBDs (disturbed sleep, nocturnal
dyspnea, snoring) or if they remain symptomatic despite
optimal medical management of congestive heart failure
(CHF). (Standard)
4.1.3.9 Patients with coronary artery disease should be
evaluated for symptoms and signs of sleep apnea. If there is
suspicion of sleep apnea, the patients should undergo a
sleep study. (Guideline)
4.1.3.10 Patients with history of stroke or transient isch-
emic attacks should be evaluated for symptoms and signs of
sleep apnea. If there is suspicion of sleep apnea, the patients
should undergo a sleep study. (Option)
4.1.3.11 Patients referred for evaluation of significant
tachyarrhythmias or bradyarrhythmias should be ques-
tioned about symptoms of sleep apnea. A sleep study is
indicated if questioning results in a reasonable suspicion
that OSA or central sleep apnea (CSA) is present.
(Guideline)
Polysomnography in Other Medical Disorders
4.2.3.1 For patients with neuromuscular disorders and
sleep-related symptoms, polysomnography is routinely
indicated to evaluate symptoms of sleep disorders that are
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214 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy
not adequately diagnosed by obtaining a sleep history, assess-
ing sleep hygiene, and reviewing sleep diaries. (Standard)
4.2.3.2 Polysomnography is not indicated to diagnose
chronic lung disease. (Standard)
Alternate Tools
4.2.5.1 Nocturnal oximetry may be helpful or sufficient in
assessing a disorder in which the only or principal clinical
issue is the level of hypoxemia and when determining sleep
stages or assessing sleep apnea is not necessary. (Standard)
4.3 Narcolepsy
4.3.3.1 Polysomnography and a multiple sleep latency test
performed on the day after the polysomnographic evaluation
are routinely indicated in the evaluation of suspected narco-
lepsy. (Standard)
4.4 Parasomnias and Seizure Disorders
4.4.1.1 A clinical history of any parasomnia must describe
and characterize the behaviors in detail with special empha-
sis on age of onset, time of night, frequency, regularity, and
duration of episodes. (Standard)
4.4.1.2 Common, uncomplicated, noninjurious parasom-
nias, such as typical disorders of arousal, nightmares, enure-
sis, sleeptalking, and bruxism, can usually be diagnosed by
clinical evaluation alone. (Standard)
4.4.1.3 A clinical history, neurologic examination, and a
routine electroencephalogram (EEG) obtained while the
patient is awake and asleep are often sufficient to establish
the diagnosis and permit the appropriate treatment of a
sleep-related seizure disorder. The need for a routine EEG
should be based on clinical judgment and the likelihood that
the patient has a sleep-related seizure disorder. (Option)
4.4.3.5 Polysomnography may be indicated when the pre-
sumed parasomnia or sleep-related seizure disorder does not
respond to conventional therapy. (Option)
4.4.3.6 Polysomnography is not routinely indicated in
cases of typical, uncomplicated, and noninjurious parasom-
nias when the diagnosis is clearly delineated. (Option)
4.4.3.7 Polysomnography is not routinely indicated for
patients with a seizure disorder who have no specific com-
plaints consistent with a sleep disorder. (Option)
4.4.4.1 The minimum channels required for the diagnosis
of parasomnia or sleep-related seizure disorder include
sleep-scoring channels (EEG, electro-oculogram [EOG],
chin electromyogram [EMG]); EEG using an expanded bilat-
eral montage; and EMG for body movements (anterior tibi-
alis or extensor digitorum). Audiovisual recording and
documented technologist observations during the period of
study are also essential. (Option)
From Kushida CA, Littner MR, Morgenthaler T, Alessi CA: Practice parameters for the indications for polysomnography and related procedures: an
update for 2005. Sleep 2005;28:499521.
4.4.4.2 Interpretation of polysomnography with video
and extended EEG montage requires skills in both sleep
medicine and seizure recognition. Polysomnographers and
electroencephalographers who are not experienced or
trained in recognizing and interpreting both polysomno-
graphic and EEG abnormalities should seek appropriate con-
sultation or should refer patients to a center where this
expertise is available. (Option)
4.4.4.3 A paper speed of at least 15 mm/sec and preferably
30 mm/sec is recommended to enhance the recognition of
seizure activity. In digital EEG recordings, the sampling rate
must be adequate to identify brief paroxysmal discharges.
(Option)
4.5 Restless Legs Syndrome and Periodic Limb
Movement Disorder
4.5.3.1 Polysomnography is indicated when a diagnosis of
periodic limb movement disorder is considered because of
complaints by the patient or an observer of repetitive limb
movements during sleep and frequent awakenings, frag-
mented sleep, difficulty maintaining sleep, or excessive
daytime sleepiness. (Standard)
4.5.3.2 Polysomnography is not routinely indicated to
diagnose or treat restless legs syndrome, except where uncer-
tainty exists in the diagnosis. (Standard)
4.5.4.1 The minimum channels required for the evalua-
tion of periodic limb movements and related arousals include
EEG, EOG, chin EMG, and left and right anterior tibialis
surface EMG. Respiratory effort, airflow, and oximetry
should be used simultaneously if sleep apnea or upper-
airway resistance syndrome is suspected to allow a distinc-
tion to be made between inherent periodic limb movements
and those limb movements associated with respiratory
events. (Standard)
4.5.4.2 Intraindividual night-to-night variability exists in
patients with periodic limb movement sleep disorder, and a
single study might not be adequate to establish this diagno-
sis. (Option)
4.6 Depression with Insomnia
4.6.3.1 Neither a polysomnogram nor a multiple sleep latency
test is routinely indicated in establishing the diagnosis of
depression. (Standard)
4.7 Circadian Rhythm Sleep Disorders
4.7.3.1 Polysomnography is not routinely indicated for the
diagnosis of circadian rhythm sleep disorders. (Standard)
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Clinical Guidelines for the Use of Unattended
Portable Monitors in the Diagnosis of Obstructive
Sleep Apnea in Adult Patients
1.1 Portable monitoring (PM) for the diagnosis of obstruc-
tive sleep apnea (OSA) should be performed only in con-
junction with a comprehensive sleep evaluation. Clinical
sleep evaluations using PM must be supervised by a practi-
tioner with Board certification in Sleep Medicine or an indi-
vidual who fulfills the eligibility criteria for the Sleep
Medicine Certification Examination. In the absence of a
comprehensive sleep evaluation, there is no indication for
the use of PM.
1.2 Provided that the recommendations of 1.1 have been
satisfied, PM may be used as an alternative to polysomnog-
raphy (PSG) for the diagnosis of OSA in patients with a high
pretest probability of moderate to severe OSA. PM should
NOT be used in patient groups described in 1.2.1, 1.2.2, and
1.2.3 (those with co-morbidities, other sleep disorders, or for
screening).
1.2.1 PM is not appropriate for the diagnosis of OSA in
patients with significant co-morbid medical conditions that
may degrade the accuracy of PM, including, but not limited
to, moderate to severe pulmonary disease, neuromuscular
disease, or congestive heart failure (CHF).
1.2.2 PM is not appropriate for the diagnostic evaluation
of OSA in patients suspected of having other sleep disorders,
including central sleep apnea, periodic limb movement dis-
order (PLMD), insomnia, parasomnias, circadian rhythm
disorders, or narcolepsy.
1.2.3 PM is not appropriate for general screening of
asymptomatic populations.
1.3 PM may be indicated for the diagnosis of OSA in
patients for whom in-laboratory PSG is not possible by
virtue of immobility, safety, or critical illness.
1.4 PM may be indicated to monitor the response to
noncontinuous positive airway pressure (CPAP) treatments
for OSA, including oral appliances, upper airway surgery,
and weight loss.
2.1 At a minimum, the PMs must record airflow, respira-
tory effort, and blood oxygenation. The type of biosensors
used to monitor these parameters for in-laboratory PSG are
recommended for use in PMs.
Appendix 13-2
2.2 The sensor to detect apnea is an oronasal thermal
sensor and to detect hypopnea is a nasal pressure transducer.
Ideally, PMs should use both sensor types.
2.3 Ideally, the sensor for identification of respiratory
effort is either calibrated or uncalibrated inductance
plethysmography.
2.4 The sensor for the detection of blood oxygen is pulse
oximeter with appropriate signal averaging time and accom-
modation for motion artifact.
3. Methodology for Portable Monitoring
3.1 PM testing should be performed under the auspices of
an American Academy of Sleep Medicine (AASM)accred-
ited comprehensive Sleep Medicine Program with policies
and procedures for sensor application, scoring, and interpre-
tation of PM. A quality/performance improvement program
for PM including interscorer reliability must be in place to
ensure accuracy and reliability.
3.2 An experienced sleep technician, sleep technologist,
or appropriately trained health care practitioner must
perform the application of PM sensors or directly educate
the patient in correct application of sensors.
3.3 PM devices must allow for the display of raw data
for manual scoring or editing of automated scoring by
a trained and qualified sleep technician/technologist.
Evaluation of PM data must include review of the raw
data by a Board-certified sleep specialist or an individual
who fulfils the eligibility criteria for sleep medicine
certification.
3.4 Scoring criteria should be consistent with current
published AASM standards for scoring apneas and
hypopneas.
3.5 Due to the known rate of false-negative PM tests,
in-laboratory polysomnography (PSG) should be performed
in cases where PM is technically inadequate or fails to estab-
lish the diagnosis of OSA in patients with a high pretest
probability.
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216 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy

3.6 A follow-up visit with a physician or other appropri- 3.7 Unattended PM can be used with the parameters
ately trained and supervised health care provider should be above in the patients home.
performed on all patients undergoing PM to discuss the
results of the test.

From Collop NA, Anderson WM, Boehlecke B, et al: Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep
DaneshGroup.com
apnea in adult patients. Portable Monitoring Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2007;3:737747.

First Coast Services Durable Medical Area
Contractor (DMAC Region I)
Local Carrier Determinations for
Polysomnography and Sleep Testing
(L29949)Excerpts
Prior to ordering the tests, the patient must have a face-to-
face clinical evaluation by a physician. The evaluation must
include:
1. A sleep history and physical examination including,
but not limited to, snoring, daytime sleepiness,
observed apneas, choking or gasping during sleep,
morning headaches; and
2. Epworth sleepiness scale; and
3. Physical examination that documents body mass
index, neck circumference, and a focused cardiopul-
monary and upper airway evaluation.
Accreditation
All centers billing sleep studies must maintain proper
certification/accreditation documentation on file that indi-
cates it is accredited by the American Academy of Sleep
Medicine (AASM) or that it is accredited as a sleep labora-
tory by the Joint Commission.
Physician Training/Certification
All sleep tests must be reviewed and the tests must be inter-
preted by either:
1. A Diplomate of the American Board of Sleep Medicine
(ABSM) OR
2. A Diplomate in Sleep Medicine by a member board of
the American Board of Medical Specialties (ABMS) OR
3. An active physician staff member of an AASM-
accredited sleep center or sleep laboratory OR
4. An active physician staff member of a Joint
Commissionaccredited sleep laboratory.
Home Sleep Testing
Type 1 PSG is covered when used to aid the diagnosis of
OSA in beneficiaries who have clinical signs and symptoms
Appendix 13-3
indicative of OSA if performed attended in a sleep laboratory
facility. Type 1 devices are capable of recordings of all of the
physiologic parameters and signals defined for PSG. The
recording is furnished in a sleep laboratory facility in which
a technologist is physically present to supervise the record-
ing during sleep time and has the ability to intervene if
needed. Minimal requirements include recording of electro-
encephalogram (EEG), electro-oculogram (EOG), chin elec-
tromyogram (EMG), anterior tibialis EMG, electrocardiogram
(ECG), airflow, respiratory effort, and oxygen saturation.
Body position must be documented or objectively measured.
Trained personnel must be in constant attendance and able
to intervene.
A type 2 sleep testing device is covered when used to aid
the diagnosis of OSA in beneficiaries who have clinical signs
and symptoms indicative of OSA if performed unattended
in or out of a sleep laboratory facility or attended in a sleep
laboratory facility. Type 2 devices are portable devices that
may measure the same channels as type 1 testing, except that
a heart-rate monitor can replace the ECG. This device has a
minimum of seven channels (e.g., EEG, EOG, EMG, ECG-
heart rate, airflow, respiratory effort, and oxygen saturation
this type of device monitors sleep staging). A sleep technician
is not necessarily in constant attendance in type 2 studies but
is needed for preparation.
A type 3 sleep testing device is covered when used to aid
the diagnosis of OSA in beneficiaries who have clinical signs
and symptoms indicative of OSA if performed unattended
in or out of a sleep laboratory facility or attended in a sleep
laboratory facility. Type 3 devices monitor and record a
minimum of four channels and must record ventilation or
airflow, heart rate or ECG, and oxygen saturation. A sleep
technician is not necessarily in constant attendance in type
3 studies but is needed for preparation.
A type 4 sleep testing device measuring three or more
channels, one of which is airflow, is covered when used to
aid the diagnosis of OSA in beneficiaries who have signs and
symptoms indicative of OSA if performed unattended in or
out of a sleep laboratory facility or attended in a sleep labora-
tory facility. Type 4 devices must include airflow as one of
the required three channels. Other measurements may
include oximetry and heart rate. A sleep technician is not
necessarily in constant attendance in type 4 studies but is
needed for preparation.
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218 Chapter 13 Polysomnography, Portable Monitoring, and Actigraphy

PAT. A sleep testing device measuring three or more indicative of OSA if performed unattended in or out of a
channels that include actigraphy, oximetry, and peripheral sleep laboratory facility or attended in a sleep laboratory
arterial tone is covered when used to aid the diagnosis facility. A sleep technician is not necessarily in constant
of OSA in beneficiaries who have signs and symptoms attendance in such studies but is needed in preparation.

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Subjective and Objective
Measures of Daytime Sleepiness
Chapter Points (see also Box 146)
The ESS measures self-rated average sleep propensity
(chance of dozing) over eight common situations. The
scale ranges from 0 to 24 with 10 or less being
considered normal.
The MSLT objectively measures the tendency to fall
asleep (MSL) and the propensity to have SOREMPs.
The MSLT consists of five naps spaced every 2 hours
beginning about 1.5 to 3 hours after the wake-up time.
The MSLT should be preceded by a PSG to detect
causes of sleepiness such as sleep apnea and to verify
adequate sleep before the MSLT. MSLT findings are not
considered reliable if less than 360 minutes of sleep is
recorded.
The MSLT diagnostic criteria for narcolepsy include an
MSL of 8 minutes or less and 2 or more SOREMPs.
However, a negative MSLT does NOT rule out narcolepsy
because the sensitivity of the MSLT for diagnosing
narcolepsy is only approximately 70% to 80%.
The MSLT diagnostic criteria for idiopathic
hypersomnia include an MSL of less than 8 minutes
and 0 to 1 SOREMPs in five naps.
Up to 6% of untreated patients with OSA will have an
MSLT meeting criteria for narcolepsy.
If narcolepsy in addition to OSA is suspected, patients
should have a PSG on CPAP to document good
treatment and adequate sleep and a subsequent MSLT
on CPAP. This assumes that OSA has been well treated
with CPAP for a period of time (e.g., documented CPAP
adherence).
Medications that may affect MSLT sleep latency
(stimulants, sedatives) or the number of SOREMPs
(REM-suppressant medications) should be withdrawn
for 10 days to 2 weeks preceding testing if possible.
The MWT objectively quantifies a patients ability to
remain awake in a situation predisposing to sleep
(dimly lighted room, sitting on a bed). The 40 minute
MWT is recommended. Each MWT nap is terminated
after 40 minutes if no sleep has been recorded; after
Chapter 14
3 consecutive epochs of stage N1, or after a single
epoch of any other sleep stage (N2, N3, or R). The sleep
latency is defined as the time from lights out until the
first epoch of any stage of sleep.
Excessive daytime sleepiness (EDS) is defined as sleepiness
that occurs in a situation when an individual would usually
be expected to be awake and alert. EDS is said to affect at
least 5% of the general population. Causes of EDS include
sleep deprivation/inadequate sleep, a number of sleep disor-
ders (obstructive sleep apnea [OSA], narcolepsy, and idio-
pathic hypersomnia), sleep disturbance from medical
conditions, and medication side effects. The periodic limb
movement disorder can be associated with EDS but is a fairly
uncommon disorder. Depression and mood disorders are
common but are more likely to be associated with insomnia
complaints than with EDS. However, up to 15% of depressed
patients may complain of daytime sleepiness. The degree of
sleepiness can be assessed by subjective and objective mea-
sures of sleepiness.
SUBJECTIVE MEASURES
Questionnaires such as the Stanford Sleepiness Scale or the
Epworth Sleepiness Scale (ESS)1,2 are measures of self-rated
symptoms of sleepiness. The Stanford Sleepiness Scale (Table
141) measures subjective feelings of sleepiness (fogginess,
beginning to lose interest in staying awake). A score above
3 is considered sleepy. In contrast, the ESS measures self-
rated average sleep propensity (chance of dozing) over eight
common situations that almost everyone encounters. The
propensity to fall asleep is rated as 0, 1, 2, or 3 where 0 cor-
responds to never and 3 to a high chance of dozing (Table
142). The maximum score is 24 and normal is assumed to
be 10 or less. ESS scores of 16 or greater are associated with
severe sleepiness.
The ESS correlates roughly with the severity of OSA
(apnea-hypopnea index [AHI]) (Table 143)2,3 and improves
(lower score) after continuous positive airway pressure
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220 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness

TABLE 141 TABLE 143

Stanford Sleepiness Scale Epworth Sleepiness Scale Scores in Mild,
Moderate, and Severe Obstructive Sleep Apnea
DEGREE OF SLEEPINESS SCALE RATING
MEAN TOTAL
Feeling active, vital, alert, or wide awake 1
AHI NUMBER ESS
Functioning at high levels, but not at 2 SEVERITY OF (MEAN OF (MEAN RANGE
peak; able to concentrate OSA (AHI) SD) SUBJECTS SD) OF ESS
Awake, but relaxed; responsive but not 3 Mild OSA 8.8 2.3 22 9.5 3.3 416
fully alert (AHI
Somewhat foggy, let down 4 515)
Foggy; losing interest in remaining 5 Moderate OSA 21.1 4.0 20 11.5 4.2 520
awake; slowed down (AHI >
1530)
Sleepy, woozy, fighting sleep; prefer to 6
lie down Severe OSA 49.5 9.6 13 16.0 4.4 823
(AHI > 30)
No longer fighting sleep, sleep onset 7
AHI = apnea-hypopnea index; ESS = Epworth Sleepiness Scale;
soon; having dreamlike thoughts
OSA = obstructive sleep apnea; SD = standard deviation.
Asleep X Adapted from Johns MW: A new method for measuring daytime sleepiness:
The Epworth Sleepiness Scale. Sleep 1991;14:540545.

TABLE 142
Epworth Sleepiness Scale
SITUATION: USUAL WAY OF LIFE CHANCE OF DOZING
10
IN RECENT TIMES SCORE 0, 1, 2, 3*
Mean Epworth Sleepiness Scale

Sitting and reading 03

9
Watching TV 03
Sitting, inactive in a public place 03
8
(e.g., a theater or a meeting)
As a passenger in a car for an hour 03
without a break 7

Lying down to rest in the afternoon 03

when circumstances permit 6
Sitting talking to someone 03
Sitting quietly after a lunch 03 5
without alcohol 5 5 to 15 15 to 30 30
In a car, while stopped for a few 03 Apnea  hypopnea index (#/hr)
minutes in traffic FIGURE 141 Epworth Sleepiness Scale increases with worsening obstructive sleep
Total 024 apnea (OSA) severity as measured by the apnea-hypopnea index (events/hr). From
Gottlieb DJ, Whitney CW, Bonekat WH, et al: Relation of sleepiness to respiratory
*0 = would NEVER doze 010 normal disturbance index. Am J Respir Crit Care Med 1999;159:502507.
1 = SLIGHT chance of dozing
2 = MODERATE chance of dozing
3 = HIGH chance of dozing
multiple sleep latency test (MSLT; an objective measure of
sleepiness discussed in the next section) in a group of sleepy
(CPAP) treatment.4 However, as noted in Table 143, there patients. However, Benbadis and colleagues5 found no cor-
is a wide range of ESS scores at any level of OSA severity. A relation between the MSLT findings and the ESS. Sangal and
large study by Gottlieb and coworkers3 found a modest cor- associates6 found a statistically significant but low negative
relation between the ESS and OSA severity in a large correlation between the ESS and the sleep latency (higher
population-based study of 1824 subjects. The degree of ESS associated with lower sleep latency) on the maintenance
daytime sleepiness in the population was relatively mild of wakefulness test (MWT) and MSLT in a large group of
(Fig. 141). Johns2 reported a significant negative correlation narcolepsy patients. A scatter plot of ESS versus sleep latency
between the ESS and the mean sleep latency (MSL) on the on the MSLT is shown in Figure 142. There was also a
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 Chapter 14
24
18
ESS
12
6 Routine evaluation of patients with OSA.
0 conditions (other than narcolepsy).
0 5 10 15
Sleep latency (min)
FIGURE 142 Scatter plot of Epworth Sleepiness Scale (ESS) score versus mean sleep
latency on the multiple sleep latency test (MSLT) in 522 drug-free patients with
narcolepsy. The line represents a quadratic fit. From Sangal RB, Mitler MM, Sangal JM:
Subjective sleepiness ratings (Epworth Sleepiness Scale) do not reflect the same parameter
of sleepiness as objective sleepiness (maintenance of wakefulness test) in patients with
narcolepsy. Clin Neurophysiol 1999;110:21312135.
modest correlation between the sleep latencies as deter-
mined by the MSLT and MWT. Of interest, the correlation
between the MSLT and the MWT latencies (r = 0.52, P <
.001) was stronger than correlations between the ESS and the
MWT or the MSLT latencies (r = 0.29, P < .001 and r =
0.27, P < .001, respectively).6
OBJECTIVE MEASURES
Multiple Sleep Latency Test
The MSLT712 is used to support a diagnosis of narcolepsy
and/or quantify the degree of daytime sleepiness. The MSL
(lights out to sleep onset) is a measure of the degree of
daytime sleepiness. The sleep latency is the time from lights
out to the beginning of the first epoch of any stage of sleep.
The test is terminated if no sleep occurs within 20 minutes
of lights out (maximum sleep latency is 20 min). After sleep
onset, the MSLT continues for 15 minutes of clock time. If
rapid eye movement (REM) sleep occurs within this time
period, a sleep-onset rapid eye movement period (SOREMP)
is said to have occurred. The MSLT criteria used to support
a diagnosis of narcolepsy are an MSL of 8 minutes or less
and 2 or more SOREMPs.13 Many factors can alter the find-
ings of the MSLT and considerable clinical judgment is
needed to avoid an error in interpretation. The MSLT may
be used in the research setting as an objective measure of
daytime sleepiness of a given population of interest or to
assess a response to treatment. The clinical indications for
the use of the MSLT (Box 141) are outlined by the current
American Academy of Sleep Medicine (AASM) practice
Subjective and Objective Measures of Daytime Sleepiness 221
BOX 141
Indications for Use of the Multiple Sleep
Latency Test
MSLT INDICATED
Confirmation of suspected narcolepsy (Standard).
Suspected idiopathic hypersomnia (Option)to help
differentiate idiopathic hypersomnia from narcolepsy.
MSLT NOT INDICATED (STANDARD)
Change in sleepiness in OSA after CPAP treatment.
Evaluation of sleepiness in medical or neurologic
Evaluation of sleepiness in insomnia.
REPEAT MSLT INDICATED (STANDARD)
Initial MSLT affected by extraneous/unusual conditions.
Appropriate study conditions not present during initial
testing.
Ambiguous or uninterpretable findings.
Clinical suspicion of narcolepsy not confirmed by an
earlier MSLT.
AASM Levels of recommendation: Standard > Guideline > Option.
AASM = American Academy of Sleep Medicine; CPAP = continuous positive
airway pressure; MSLT = multiple sleep latency test; OSA = obstructive sleep
apnea.
From Littner MR, Kushida C, Wise M, et al: Practice parameters for clinical use
of the multiple sleep latency test and the maintenance of wakefulness test.
Sleep 2005;28:113121.
parameters concerning the use of the MSLT10 and prior
guidelines published by this organization.8,9
A standard-level recommendation states the MSLT is a
validated objective measure of the ability or tendency to fall
asleep. As mentioned previously, the sleep latency is the
parameter that reflects the degree of daytime sleepiness. The
MSLT is indicated for evaluation of patients with suspected
narcolepsy or idiopathic hypersomnia, but NOT for evalua-
tion of OSA patients before or after treatment, or to quantify
sleepiness in patients with insomnia, medical, or neurologic
disorders (other than narcolepsy). The practice parameters
also outlined conditions under which a repeat MSLT is indi-
cated. These include a prior MSLT with unusual conditions
or if the initial MSLT was negative in a patient with a strong
clinical suspicion of narcolepsy (see Box 141).
MSLT Protocol
A standardized MSLT protocol performed by an experienced
sleep technologist (Boxes 142 and 143) is required to
obtain accurate testing results. A four-nap MSLT is not reli-
able for the diagnosis of narcolepsy unless 2 SOREMPs have
occurred after four naps. Even then, a five-nap MSLT is sug-
gested because the physician reading the study may disagree
with the technologists assessment of SOREMPs. A technolo-
gist experienced in performing the MSLT is essential.811 The
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222 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness
BOX 142
Multiple Sleep Latency Test ProtocolPart 1
A PSG during the patients normal major sleep period
MUST precede the MSLT.
A minimum of 360 min of sleep during the PSG is
required for a valid MSLT.
Five nap opportunities at 2-hr intervals.
Initial nap 1.53 hr after termination of nocturnal PSG.
MSLT should NOT follow a split-sleep study.
Sleep log may be obtained for 1 wk before the MSLT to
assess sleep-wake schedule.
IMPORTANT CONSIDERATIONS
Stimulants, stimulant-like medications, and REM-
suppressing medications should be stopped 2 wk before
the MSLT (or at least a time period > five times the medica-
tion half-life).
Other medications should be adjusted as needed to
minimize sedating or stimulating properties.
Room temperature should be adjusted for patient
comfort.
Study room should be dark and quiet during testing.
Drug screening is usually performed on the morning of
the MSLT (or after if clinically indicated).
Smoking should be stopped at least 30 min before each
nap.
Patient must abstain from caffeinated beverages and
avoid unusual exposure to bright light.
Avoid vigorous physical activity. Stimulating activity
should cease at least 15 min before naps.
Recommended montage: frontal, central, and occipital
EEG derivations, left and right EOG, mental/submental
EMG, and ECG.
ECG = electrocardiogram; EEG = electroencephalogram; EMG =
electromyogram; EOG = electro-oculogram; MSLT = multiple sleep latency
test; PSG = polysomnography; REM = rapid eye movement.
From Littner MR, Kushida C, Wise M, et al: Practice parameters for clinical use
of the multiple sleep latency test and the maintenance of wakefulness test.
Sleep 2005;28:113121.
technologist is required to accurately score sleep in real time.
Of note, polysomnography (PSG) must precede the MSLT.
This is required to rule out causes of sleepiness such as sleep
apnea and to document an adequate amount of sleep preced-
ing the MSLT. An adequate total sleep time during the PSG
is needed for valid MSLT results. At least 360 minutes of
sleep must be recorded for the MSLT findings to be reli-
able. A very high percentage of REM sleep (% of total sleep
time) on the PSG should alert the physician to the possibility
of REM rebound. This might be a clue to the recent with-
drawal of a REM-suppressing medication or prior sleep
deprivation. A sleep diary for 1 to 2 weeks before the MSLT
may be helpful in documenting the adequacy of preceding
sleep. Preceding sleep deprivation can result in shortened
sleep latency.11,12 Some patients may need a total sleep time
BOX 143
Multiple Sleep Latency Test ProtocolPart 2
NAP PROTOCOL
Before each nap, patient should be asked if he or she needs
to go to the bathroom.
Biocalibration instructions*: (1) Lie quietly with your eyes
open for 30 sec, (2) close both eyes for 30 sec, (3) without
moving your head, look to the right, then left, then right,
then left, right, and then left, (4) blink eyes slowly for five
times, (5) clinch or grit your teeth tightly together.
Start every nap with these instructions:
Please lie quietly, assume a comfortable position, keep
your eyes closed and try to fall asleep.
After these instructions, bedroom lights are turned off.
A nap is terminated after 20 min if sleep does not occur.
MSLT continues for 15 min of clock time after sleep
onset (to detect SOREMP).
Between naps, the patient is out of bed and prevented
from sleeping (observation by staff ).
A light breakfast is recommended at least 1 hr before the
first trial. A light lunch is recommended immediately after
the second nap. (Meals before nap 1 and after nap 2.)
MSLT DEFINITIONS AND REPORT
DEFINITIONS
Sleep latencytime from lights off to the start of the first
epoch of any stage of sleep (including stage N1). If no sleep
is noted, the sleep latency is recorded as 20 min.
REM latencytime from the beginning of the first epoch
of sleep to the beginning of the first epoch of REM sleep.
MSLT REPORT
Start and stop times of each nap.
Sleep latency of each nap and MSL for the MSLT.
Number of SOREMPs (>15 sec of REM sleep in any 30-sec
epoch).
Events that represent a deviation from the standard MSLT
protocol.
*The standard in most sleep centers is to ask for the patient to look up and
down as well as right and left.
MSL = mean sleep latency; MSLT = multiple sleep latency test; REM = rapid
eye movement; SOREMPs = sleep-onset rapid eye movement periods.
From Littner MR, Kushida C, Wise M, et al: Practice parameters for clinical use
of the multiple sleep latency test and the maintenance of wakefulness test.
Sleep 2005;28:113121.
longer than 360 minutes during the PSG and during the
weeks before the MSLT to normalize the MSL.12,14 A urine
drug screen may help identify surreptitious medication use
that can affect the MSLT results. Cigarette smoking should
stop at least 30 minutes before each nap (Table 144). Vigor-
ous physical activity should be avoided and any stimulating
activity stopped at least 15 minutes before each nap. The
patient should be asked whether she or he needs to use the
bathroom before the nap is scheduled to begin. Between
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 Chapter 14
TABLE 144
Multiple Sleep Latency Test Timetable:
Before Testing
2 weeks Stop REM suppressing medications,
stimulants, and stimulant-like medications.
(12 wk) Keep sleep diary and obtain adequate sleep
and regular routine.
1 day PSG during regular sleep period precedes
MSLT.
30 min Stop tobacco smoking.
15 min Stop stimulating activity.
10 min Comfortable clothing, visit restroom if needed.
5 min Calibration series.
30 sec Assume comfortable position for sleep.
5 sec Please lie quietly, assume a comfortable
position, keep your eyes closed and try
to fall asleep.
0 sec Lights out
MSLT = multiple sleep latency test; PSG = polysomnography; REM = rapid eye
movement.
naps, the subject should be out of bed and observed in order
to prevent sleep between the naps. A light breakfast was
recommended at least one hour before the first nap and a
light lunch immediately after the second nap. A typical
MSLT schedule might include wake-up 6:007:00 am, break-
fast, nap 1 at 9:00 am, nap 2 at 11:00 am, light lunch, nap 3
at 1:00 pm, nap 4 at 3:00 pm, nap 5 at 5:00 pm.
Other MSLT Considerations
Although not specifically addressed in the recent AASM
practice parameters, it is usual practice to have patients
change out of night clothes before nap testing begins. This
was the recommendation in earlier published guidelines for
the MSLT.8,9 As untreated OSA can be associated with MSLT
findings consistent with narcolepsy,15 adequate treatment of
sleep apnea (for a sufficient time period to allow for symptom
improvement) should precede MSLT evaluation for narco-
lepsy. If narcolepsy is suspected in a patient being treated for
sleep apnea (e.g., with CPAP or an oral appliance), PSG is
usually performed on CPAP/oral appliance treatment. The
PSG documents adequate treatment of sleep apnea and at
least one night of adequate sleep before the MSLT. Although
not addressed in the recent MSLT practice parameters, the
1992 AASM MSLT guidelines stated To determine the con-
current presence of narcolepsy after treatment of the obstruc-
tive sleep apnea syndrome by CPAP, the MSLT should be
performed with the patient using the CPAP device. In this
case, recording of machine flow is often performed in addi-
tion to electroencephalogram (EEG), electro-oculogram
(EOG), chin electromyogram (EMG), and electrocardio-
gram (ECG). It is also worth mentioning that if unequivocal
Subjective and Objective Measures of Daytime Sleepiness 223
TABLE 145
Multiple Sleep Latency Facts*
MSL (MIN) (MEAN SD)
Normal 10.4 4.3 (four naps)
11.6 5.2 (five naps)
Narcolepsy 3.1 2.9
Idiopathic 6.2 3.0
hypersomnia
Sleep apnea 7.2 6.0
PROPORTION OF POPULATIONS WITH SHORT MSLS
30% of normal individuals have an MSL < 8 min.
16% of normal individuals have an MSL < 5 min.
16% of patients with narcolepsy have an MSL > 5 min.
*MSLT MSL in normal and patient groups.
MSL = mean sleep latency; MSLT = multiple sleep latency test; SD = standard
deviation.
Data from Littner MR, Kushida C, Wise M, et al: Practice parameters for clinical
use of the multiple sleep latency test and the maintenance of wakefulness
test. Sleep 2005;28:113121; Arand D, Bonnet M, Hurwitz T, et al: A review by
the MSLT and MWT Task Force of the Standards of Practice Committee of the
AASM. The clinical use of the MSLT and MWT. Sleep 2005;28:123144; and
Aldrich MS, Chervin RD, Malow BA: Value of the multiple sleep latency test
(MSLT) for the diagnosis of narcolepsy. Sleep 1997;20:620629.
cataplexy is present in a patient with OSA, a diagnosis of
concurrent narcolepsy can be made in the absence of confir-
matory MSLT findings (see Chapter 24).
MSL Values in Normal Populations and Patients
Traditional gradations of the MSL considered a value less
than 5 minutes to denote severe sleepiness and a value less
than 10 minutes to denote pathologic sleepiness.8,9 A normal
MSL was often stated to be greater than 15 minutes (1015
was termed a gray zone). However, a recent large systematic
review and meta-analysis of MSLT studies found the average
MSL in normal individuals to be just above 10 minutes11
(Table 145), with many normal individuals having an MSL
less than 10 minutes.
The MSL values for studies of groups of patients with the
major sleep disorders associated with daytime sleepiness
published from a large analysis11 are listed in Table 145.
Patients with narcolepsy had the shortest MSL. The sleep
latency of patients with idiopathic hypersomnia and OSA is
usually between 5 and 10 minutes. Of interest, up to 30% of
normal populations have an MSL of 8 minutes or less. An
MSL value of 8 minutes or less is part of the International
Classification of Sleep Disorders, 2nd edition (ICSD-2) cri-
teria for diagnosis of narcolepsy and less than 8 minutes for
the diagnosis of idiopathic hypersomnia.13 Previously, a sleep
latency of less than 5 minutes was the criterion.8,9,12 The
ICSD-213 chose an MSL of 8 minutes rather than 5 minutes
as a diagnostic criteria to improve the sensitivity of the MSLT
for the diagnosis of narcolepsy.12 About 16% of narcoleptics
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 224 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness

have an MSL greater than 5 minutes and 16% of normal is medically practical. Abrupt withdrawal before the study
controls have an MSL below 5 minutes.11,13 should also be avoided.

Factors Affecting the MSLT MSL Number of SOREMPs

A number of factors can affect the sleep latency during the
MSLT (Box 144). The time of day of the nap affects the sleep
latency. Of note, the shortest sleep latency tends to be in the
third or fourth nap (early afternoon)7 (Fig. 143). The MSL
for a five-nap MSLT is slightly higher than that for a four-nap
MSLT. The sleep latency on the last nap is often the highest
and may reflect anticipation of the end of the test (anticipa-
tion of leaving the sleep center). Interpretation of the MSLT
can be problematic in shift workers or late sleepers. The MSL
increases with increasing age (Fig. 144). The normative
MSLT results for children are discussed in a later section.
Medications (stimulants or sedatives) that could affect the
MSL should be withdrawn 2 weeks before the MSLT if this
The occurrence of REM sleep within 15 minutes of sleep
onset (SOREMP) is more specific for the diagnosis of narco-
lepsy than an MSL of 8 minutes or less. Studies of normal
populations have found 0 to 1 SOREMPs in five naps.7,11
However, SOREMPs can occur in normal individuals with
prior sleep or REM sleep deprivation, in untreated OSA, and
when there is a circadian phase delay (Box 145). Patients
with depression or other psychiatric disorders can also have
a short REM latency. In general, the number of MSLT
SOREMPs increases as the sleep latency decreases.11 Those
disorders associated with SOREMPs during the MSLT may
also be associated with a short nocturnal REM latency.12

BOX 144 16
Factors Known to Affect the MSL 15
Age.
14
Sleep latency (minutes)

MSL on five-nap MSLT > four-nap MSLT.

Shift work, delayed sleep phase (circadian factors). 13
Medications affecting MSL (stimulants or sedating
medications). 12
Prior sleep deprivation or fragmentation.
11
MSL = mean sleep latency; MSLT = multiple sleep latency test.
10

8
10 20 30 40 50 60 70 80
16 Age (yr)
15
14
FIGURE 144 Effects of age on the mean sleep latency (MSL) during the MSLT in
13 normal individuals. The MSL increases with age. A linear regression is shown. From
Sleep latency (minutes)

12 Arand D, Bonnet M, Hurwitz T, et al: A review by the MSLT and MWT Task Force of the
11 Control
Standards of Practice Committee of the AASM. The clinical use of the MSLT and MWT. Sleep
10 2005;28:123144.
9
8
7
6
5
4
Narcolepsy BOX 145
3
2
1 Causes of Sleep-Onset Rapid Eye Movement
0 Periods
00

00

00

00

00

Narcolepsy
0:

4:

6:

8:
12
-1

-1

-1

-1
0-

Untreated OSA
10

30

30

30
:3
:

:
09

11

13

15

17

Prior sleep and REM sleep deprivation/fragmentation

Nap time
Depression
FIGURE 143 Variation in sleep latency during the day in control and narcolepsy Acute withdrawal of REM-suppressing medications (tricyclic
patients. Note the naps in the afternoon have the shortest sleep latency. From antidepressants, serotonin reuptake inhibitors, lithium)
Richardson GS, Carskadon MA, Flagg W: Excessive daytime sleepiness in man: multiple Delayed circadian phase
sleep latency measurements in narcoleptic and control subjects. Electroencephalogr Clin
OSA = obstructive sleep apnea; REM = rapid eye movement.
Neurophysiol 1978;45:621627.
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 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness 225

TABLE 146
Multiple Sleep Latency Test Findings in Patients Evaluated for Daytime Sleepiness
NARCOLEPSY WITH NARCOLEPSY WITHOUT SLEEP-RELATED BREATHING
CATAPLEXY CATAPLEXY* DISORDER
N 106 64 1251
MSL < 5 min 87% 81% 39%
MSL < 8 min 93% 97% 63%
2 SOREMPs 74% 91% 7%
2 SOREMPs + 67% 75% 4%
MSL < 5 min
2 SOREMPs + 71% 91% 6%
MSL < 8 min
SOREMP on PSG 33% 24% 1%
*Diagnosis made in patients with narcolepsy without cataplexy by repeat MSLT (if necessary).
MSL = mean sleep latency; MSLT = multiple sleep latency test; PSG = nocturnal polysomnography; SOREMPs = sleep-onset rapid eye movement periods.
From Aldrich MS, Chervin RD, Malow BA: Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep 1997;20:620629.

Utility of the MSLT for Diagnosis of Narcolepsy TABLE 147

A recent review of the MSLT11 that analyzed available study Multiple Sleep Latency Test Findings in Children
data found that 2 or more SOREMPs were associated with a and Adolescents
sensitivity of 0.78 and specificity of 0.93 for the diagnosis STAGE OF MEAN SLEEP STANDARD
of narcolepsy. Aldrich and coworkers12 published their MSLT DEVELOPMENT LATENCY (MIN) DEVIATION
findings on a large number of patients with suspected nar-
colepsy (Table 146). If an initial MSLT was not diagnostic Tanner stage 1 19.0 1.8
but narcolepsy was suspected clinically, repeat MSLT testing Tanner stage 2 18.5 2.1
was performed. The study showed that patients with OSA
Tanner stage 3 16.5 2.8
can have a very short sleep latency and 2 or more SOREMPs
(although the proportion of OSA patients is much lower Tanner stage 4 15.5 3.3
compared with narcolepsy).12 In this study, about 63% of Tanner stage 5 16.1 1.5
patients with sleep-related breathing disorders have an MSL
Older adolescents 15.7 3.5
less than 8 minutes whereas only 7% had 2 or more
From Carskadon M: The second decade. In Gulleminault C (ed): Sleeping and
SOREMPs. The study also showed that a significant propor- Waking DisordersIndications and Techniques. Boston: Butterworths, 1982,
tion of patients with a narcolepsy + cataplexy can have a pp. 99125.
negative MSLT.

Normative MSLT Findings in Children and Adolescents

Limited normative MSLT information for children and ado-
lescents exists. The majority of what is known on this topic
comes from the work of Carskadon and colleagues.16,17 Table
147 presents sleep latency data from children and preado-
lescents (Tanner stages IV) as well as older adolescents.16
Of note, the older adolescents in this study had a sleep period
of 10:00 pm to 8:00 am. The sleep latency of children and
preadolescents was significantly longer than that of adoles-
cents. Of note, many children who no longer take daily naps
may not sleep at all during any MSLT nap. Therefore, the
adult criteria of an MSL of 8 minutes or less for a diagnosis
of narcolepsy in adults may not identify children with nar-
colepsy. For example, a 10-year-old child with an MSL of 12
minutes or less is considered to have evidence of daytime
sleepiness. Many adolescents go to bed later (and wake up
earlier on school days) so the data listed in Table 147 may
not apply to them. With such a compressed weekday sleep
period, they would be expected to have a shorter sleep
latency than is shown in Table 147.
In addition to having a shorter sleep latency, adolescents
frequently have a delayed circadian phase, with most teenag-
ers having bedtimes between 10:30 to 11:00 pm or later. In
one study of the MSLT in 10th graders (26 subjects), 2
SOREMPs was seen in 16% of the participants and one REM
episode was noted in 48%.17 The majority of the SOREMPs
were in the morning naps. Therefore, one must be cautious
in making the diagnosis of narcolepsy in adolescents based
on SOREMPs that occur only in the first two naps.
Clinical Examples of MSLTs
Clinical Example #1 The results of a typical five-nap MSLT are
presented in tabular form to illustrate specific points (see
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226 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness

TABLE 148 TABLE 1410

Nap 1 Nap 3
Epoch 30 31 32 33 34 35 36 37 38 39 Epoch 30 31 32 33 34 35 36 37 38 39
Stage LO W W W 1 2 2 2 3 3 Stage LO W W 1 1 2 2 2 3 3
Epoch 40 41 42 43 44 45 46 47 48 49 Epoch 40 41 42 43 44 45 46 47 48 49
Stage W 1 2 3 R R W 1 2 2 Stage W 1 2 3 W 1 W 1 2 2
Epoch 50 51 52 53 54 55 56 57 58 59 Epoch 50 51 52 53 54 55 56 57 58 59
Stage R R 1 1 2 2 2 3 3 3 Stage 2 2 3 3 3 3 3 W 1 1
Epoch 60 61 62 63 64 65 66 67 68 69 Epoch 60 61 62 63 64 65 66 67 68
Stage 3 3 3 3 Stage 1 W W
LO = lights out; R = rapid eye movement; W = wake. LO = lights out; W = wake.

TABLE 149 TABLE 1411

Nap 2 Nap 4
Epoch 30 31 32 33 34 35 36 37 38 39 Epoch 30 31 32 33 34 35 36 37 38 39
Stage LO W W W W W W W W W Stage LO W W W 1 2 2 W W W
Epoch 40 41 42 43 44 45 46 47 48 49 Epoch 40 41 42 43 44 45 46 47 48 49
Stage W W W W W W W W W W Stage R R W 3 W 1 W 1 2 2
Epoch 50 51 52 53 54 55 56 57 58 59 Epoch 50 51 52 53 54 55 56 57 58 59
Stage W W W W W W W W W W Stage 2 2 3 3 3 3 3 W 1 1
Epoch 60 61 62 63 64 65 66 67 68 69 Epoch 60 61 62 63 64 65 66 67 68
Stage W W W W W W W W W W Stage 1 W W W
Epoch 70 71 LO = lights out; R = rapid eye movement; W = wake.

Stage W
LO = lights out; W = wake.
TABLE 1412
Nap 5
Epoch 30 31 32 33 34 35 36 37 38 39
Tables 148 to 1412). In the tables, the lights out time (LO)
is assumed to be at the end of the epoch listed. The epochs Stage LO W W W W 2 W 1 2 3
are 30 seconds in duration. The light gray shading marks the Epoch 40 41 42 43 44 45 46 47 48 49
sleep latency, and the dark gray the REM latency.
Stage W 1 2 3 R R W 1 2 2
Nap 1 In nap 1, the sleep latency is 1.5 minutes (start of Epoch 50 51 52 53 54 55 56 57 58 59
epoch 34start of epoch 31) and the REM latency is 10 Stage 2 R R R 1 2 3 W 1 1
epochs or 5 minutes (start of epoch 44start of epoch 34).
Epoch 60 61 62 63 64 65 66 67 68
The MSLT continues for 15 minutes of clock time after sleep
onset to start of epoch 64 (start of epoch 34 + 30 epochs = Stage 1 W W W W
to start of epoch 64) (Table 148). LO = lights out; R = rapid eye movement; W = wake.

Nap 2 In nap 2, no sleep occurs for 20 minutes after LO.

The nap is terminated and the sleep latency is 20 minutes
(start of epoch 31 + 40 epochs = start of epoch 71) (Table
149).
Nap 3 In nap 3, the sleep latency is 1 minute (start of epoch
33start of epoch 31). Even if there is intervening wake, the
test continues for 15 minutes of clock time (30 epochs) after
the start of sleep (start of 33 + 30 = start of epoch 63). In this
nap, no stage R (REM sleep) was noted (Table 1410).
Nap 4 In nap 4, the sleep latency is 1.5 minutes. Although
stage W occurs after sleep onset, the REM latency is still the
time from the start of sleep until the start of stage R [(epoch
40epoch 34) = 6 epochs or 3.0 min]. The MSLT continues
for 30 epochs after the start of sleep (start of epoch 34 + 30
= start of epoch 64) (Table 1411).
Nap 5 In nap 5, the first epoch of sleep is epoch 35. The sleep
latency is 4 epochs or 2 minutes (start of epoch 35start of
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 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness 227

TABLE 1413
Example of a Multiple Sleep Latency Test Report
REM
NAPS LIGHTS OUT LIGHTS ON SLEEP LATENCY (MIN) REM (YES OR NO) LATENCY (MIN)
1 8:10 am 8:24:30 am 1.5 1 5.0
2 10:05 am 10:25 am 20.0 0 N/A
3 12:05 pm 12:21 pm 1.0 0 N/A
4 2:06 pm 2:22:30 pm 1.5 1 3.0
5 4:08 pm 4:15 pm 2.0 1 4.5
Mean: 5.2 SOREMPs: 3
N/A = not applicable; REM = rapid eye movement; SOREMP = sleep-onset rapid eye movement period.

100 V
EPOCH 10
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
EPOCH 11

F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin

FIGURE 145 Two 30-second epochs of sleep during an MSLT. Lights out was at the end of epoch 9. Epochs 10 and 11 are stage W.

epoch 31 = 4 epochs). The first epoch of stage R is epoch 44.
Therefore, the REM latency is 9 epochs or 4.5 minutes. The
MSLT continues for 30 epochs after sleep onset until the start
of epoch 65 (start of epoch 35 + 30 = start of epoch 65) (Table
1412).
A summary of the data from these naps appears in Table
1413.
The typical MSLT report summarizes the reason for per-
forming the test, pertinent findings on the preceding PSG,
associated findings from the sleep diary and urine drug
screen, and a interpretation of the MSLT findings. The time
of the start of each nap should also be specified along with
any unusual circumstances or deviations from the standard
protocol.
Clinical Example #2 Thirty-second epochs during an MSLT
(epoch numbers 1015) are shown in Figures 145 to 147.
LO is assumed to have occurred at the end of epoch 9.
Because epoch 12 is the first epoch of sleep (stage N1), the
sleep latency is 1 minute. The REM latency is determined by
the time from the start of epoch 12 to the start of REM sleep.
The first epoch of REM sleep is epoch 15. Therefore, the
REM latency is 3 epochs or 1.5 minutes.
Maintenance of Wakefulness Test
The MWT was designed to test the patients ability to stay
awake.10,11,18 The recent AASM practice parameters10 regard-
ing the MWT state:
1. The MWT is a validated objective measure of the ability
to stay awake for a defined time. (Standard)
2. The MWT is used in association with clinical history to
assess the ability to maintain wakefulness. (Standard)
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228 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness

100 V
EPOCH 12
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
EPOCH 13

F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin

FIGURE 146 The next two 30-second epochs of the MSLT starting in Figure 145. Epochs 12 and 13 are stage N1. Epoch 12 is sleep onset.

100 V
EPOCH 14
1 sec
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
EPOCH 15

F4-M1
C4-M1
O2-M1

E1-M2
E2-M2
Chin

FIGURE 147 Continuation of the MSLT starting in Figure 145. Epoch 14 is stage N2 and epoch 15 is stage R.

3. The MWT 40-minute protocol is recommended when
the sleep clinician requires objective data to assess
an individuals ability to remain awake. (Option)
Although the MWT has been used in both the
20-minute and the 40-minute versions,1820 the longer test
was recommended by the AASM practice parameters.
The MWT has been used to assess the effects of sleep
disturbance and treatment on the ability of patients to
stay awake as reflected by the MSL.11,1820 The study is
believed to assess different information than can be
attained with the MSLT.21 For example, some patients
with a short MSLT sleep latency may have a normal
MWT sleep latency. In research, the MWT is often used
to document the effects of treatment from alerting
agents.22 The AASM practice parameters for the use of
the MWT list specific indications as summarized in the
following paragraph.10
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 Chapter 14
Specific Indications for the Use of the MWT
The AASM practice parameters for the use of the MWT list
specific indications10:
1. The MWT 40-minute protocol may be used to assess an
individuals ability to remain awake when his or her ability
to remain awake constitutes a public or personal safety
issue. (Option)
2. The MWT may be indicated in patients with excessive
sleepiness to assess response to treatment. (Guideline)
MWT Protocol
The MWT protocol recommended by the AASM practice
parameters10 is outlined in Table 1414. The 40-minute nap
protocol is recommended. A four-nap protocol is standard.
Note that the sleep latency is defined as the time from LO
to the start of any epoch of sleep. The requirement of a
preceding PSG is left up to the clinician. In contrast to the
MSLT, during the MWT, the patient sits upright in bed (head
and shoulders comfortably supported) and the instruction
before LO is Please sit still and remain awake for as long as
possible. Look directly ahead of you, and do not look directly
at the light. Of note, it is essential that the testing individual
be observed and not allowed to use extreme measures
(hitting, moving in bed) to maintain alertness.
Each MWT nap lasts a maximum of 40 minutes after LO.
The nap is terminated if no sleep has occurred in 40
minutes or if three consecutive epochs of stage N1 are
noted or any single epoch of other stages of sleep. A low-
intensity light is present behind the patients head just out of
the visual field (usually a nightlight). The MWT definitions
and recommended information to be included in the MWT
report are listed in Table 1415.
MWT Normative Data
Normative data for the MWT from a systematic review of
MWT studies are displayed in Table 1416. Using the
40-minute MWT, 59% of patients were able to stay awake for
40 minutes on each nap. The 95% lower confidence limit was
8 minutes (97.5% had MSL > 8 min). Conversely, these data
do little to set a standard for individuals in whom alertness
is essential for personal and public safety. Certainly, staying
awake for all trials is an appropriate expectation for individu-
als requiring the highest level of safety. Therefore, whereas a
MSL less than 8 minutes is abnormal, an MSL of 8 to 40
minutes is of uncertain significance. A normal MWT
finding is no guarantee of what will happen in the work
environment. The ability to maintain alertness (different
than the ability to maintain wakefulness) may depend on
adherence to treatment, prior total sleep time, medication
side effects, and circadian factors. Of note, the sleep latency
on the MWT increases with age similar to the sleep latency
on the MSLT.11
Relationship between the MSLT and the MWT
Some of the differences in MSLT and MWT protocols are
outlined in Table 1417. When Sangal and associates21
Subjective and Objective Measures of Daytime Sleepiness 229
TABLE 1414
Maintenance of Wakefulness Test Protocol
Four trials of MWT 40-min protocol are recommended.
Four trials at 2-hr intervals.
MWT begins 1.53 hr after the patients usual wakeup
time (0900 or 1000 hr).
Performance of a PSG is not requiredneed decided by
clinician based on clinical circumstances.
Sleep log not requiredneed decided by clinician based
on clinical circumstances.
ROOM CONDITIONS
Light source positioned behind the subjects head such
that it is just out of his or her field of vision and should
deliver an illuminance of 0.100.13 lux at the corneal level
(a 7.5-W night light can be used, placed 1 ft off the floor
and 3 ft laterally removed from the subjects head).
Room temperature for patient comfort.
Subject seated in bed, the back and head supported by a
bedrest (bolster pillow) such that the neck is not
uncomfortably flexed or extended.
OTHER CONSIDERATIONS
Drug screening may be indicated. If ordered, it is usually
performed on the morning of MWT (timing can be
changed by clinician).
Conventional recording montage for MWT includes
frontal, central, occipital EEG as well as right and left EOGs,
chin EMG, ECG.
MWT NAP PROTOCOL
The patient should be asked if she or he needs to go to
the bathroom.
Biocalibration instructions: (1) Lie quietly with your eyes
open for 30 sec, (2) close both eyes for 30 sec, (3) without
moving your head, look to the right, then left, then right,
then left, right, and then left, (4) blink eyes slowly for five
times, (5) clinch or grit your teeth tightly together.
Light breakfast is recommended at least 1 hr before the
first trial.
A light lunch is recommended immediately after
termination of the second/noon trial.
Instructions: Please sit still and remain awake for as
long as possible. Look directly ahead of you, and do
not look directly at the light.
Trials are ended after 40 min if no sleep occurs, or after
unequivocal sleep, defined as three consecutive epochs of
stage 1 sleep or one epoch of any other sleep stage.
Patients are not allowed to use extraordinary measures to
stay awake such as singing or slapping the face.
ECG = electrocardiogram; EEG = electroencephalogram;
EMG = electromyogram; EOG = electro-oculogram; MWT = maintenance of
wakefulness test; PSG = polysomnography.
From Littner MR, Kushida C, Wise M, et al: Practice parameters for clinical use
of the multiple sleep latency test and the maintenance of wakefulness test.
Sleep 2005;28:113121.
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230 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness

TABLE 1415 TABLE 1417

Maintenance of Wakefulness Test Definitions and Comparisons of Multiple Sleep Latency Test and
Maintenance of Wakefulness Test Report Maintenance of Wakefulness Test
DEFINITIONS MSLT MWT
Sleep onset defined as the time from lights out to the first Naps/trials 5 4
epoch of > 15 sec of cumulative sleep in a 30-sec epoch.
Nap/trial times 2-hr intervals 2-hr intervals
If no sleep, MSL reported at 40 min. starting 1.53 hr starting
MWT REPORT
after PSG ends. 1.53 hr after
wakeup time.
Start and stop times for each trial.
Preceding PSG Required. If clinically
Sleep latency. indicated.
Total sleep time. Sleeping posture Ad lib, supine, Sitting up in bed
Stages of sleep achieved for each trial. lateral. with head
supported.
MSLarithmetic mean of the four trials.
End test No sleep for No sleep for
MSL = mean sleep latency; MWT = maintenance of wakefulness test.
20 min after start 40 min after
of study. start of study.
After 15 min from After first epoch
onset of first stage of unequivocal
TABLE 1416 of sleep (clock sleep (three
Normative Data for Maintenance of Wakefulness time). consecutive
Test (40-min Naps) epochs of stage
N1 or a single
MSL (mean SD) 30.4 11.2 min (mean SD) epoch of any
other stage of
MSL upper limit 95% 40 min
sleep).
confidence limits
Sleep latency First epoch of sleep. First epoch of
MSL lower limit 95% 8 min
sleep (15
confidence limits
consecutive
MSL > 8 min 97.5% of normal individuals sec in a 30-sec
epoch).
MSL = 40 min (able to stay 59% of normal individuals
awake during all naps) REM periods Monitoring for N/A
MSL = mean sleep latency; SD = standard deviation. 15 min of clock Amount of all
From Arand D, Bonnet M, Hurwitz T, et al: A review by the MSLT and MWT time after sleep stages of sleep
Task Force of the Standards of Practice Committee of the AASM. The clinical onset to detect specified in
use of the MSLT and MWT. Sleep 2005;28:123144.
SOREMPs. report.
Additional Sleep logs may be No guidance.
considerations obtained for
1 wk before MSLT.
administered both the MSLT and the MWT to a group of Stop cigarette No guidance.
patients with EDS, the correlation between the MSL on the smoking at least
two tests was significant but low (r = 0.41, P < .001). Several 30 min before
individuals did not fall asleep during the MWT but had some nap.
degree of daytime sleepiness as assessed by the MSLT. Table Abstain from No guidance.
caffeine day of
1418 illustrates classifications of a group of OSA patients
study.
by MSL (low or high) on a four-nap MSLT and MWT. The Stop stimulating No guidance.
study found that 15% of the patients were sleepy (MSLT MSL activities
low) but able to stay awake (MWT MSL high) (Fig. 148 and including
Table 148). vigorous activity
for at least 15 min
MSLT and MWT Changes with Treatment Both the MSLT and the before nap
MWT have been used to assess the efficacy of treatment in MSLT = multiple sleep latency test; MWT = maintenance of wakefulness test;
patients with disorders of daytime sleepiness such as OSA N/A = not applicable; PSG = polysomnography; REM = rapid eye movement;
SOREMPs = sleep-onset rapid eye movement periods.
and narcolepsy.1923 In one study by Poceta and coworkers,19
the MWT sleep latency increased from 18 to 31 minutes in
a group of patients with OSA after adequate CPAP treatment.
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 Chapter 14
TABLE 1418
Comparison of Multiple Sleep Latency Test and
Maintenance of Wakefulness Test in Sleep Apnea
Patients (N = 170)*
Sleep apnea MWT MSL low MWT MSL high
MSLT MSL high 15% 34%
MSLT MSL low 36% 15%
Note: 15% of patients were in the sleepiest group by MSLT, but by MWT were
in the group better at maintaining wake.
*Cutoff low and high MSLT and MWT based on median values for the studies
(7.5-min MSL on the MSLT and 30-min MSL on the MWT).
MSL = mean sleep latency; MSLT = multiple sleep latency test;
MWT = maintenance of wakefulness test.
From Sangal RB, Thomas L, Mitler MM: Maintenance of wakefulness test and
multiple sleep latency test: measurements of different abilities in patients
with sleep disorders. Chest 1992;101:898902.
20
15
MSLT mean
10
5 ness after treatment. However, in a large study of the effect
0 significantly improved compared with placebo at a dose of
0 10 20 30 40
MWT mean
FIGURE 148 MSL (min) on the MSLT versus MSL on the maintenance of wakefulness
test (MWT). The vertical and horizontal lines divide MSLT and MWT into low and high
quadrants. The horizontal line is the median sleep latency of the MSLT (7.5 min). The
vertical line is the median sleep latency on the MWT (30 min). From Sangal RB, Thomas
L, Mitler MM: Maintenance of wakefulness test and multiple sleep latency test:
measurements of different abilities in patients with sleep disorders. Chest 1992;101:
898902.
A recent meta-analysis of patients with mild to moderate
OSA undergoing CPAP treatment found an improvement in
the ESS (subjective sleepiness) by 1.2 points and an improve-
ment in the sleep latency on the MWT (2.1 min). A signifi-
cant change in the sleep latency by the MSLT was not
detected.20 Another meta-analysis that included patients
with severe OSA found an improvement in the ESS of 2.94
points more than placebo for the entire group.4 For patients
with AHI greater than 30 or ESS greater than 11, the ESS
improved by 4.75 points. The MWT and MSLT data were
pooled and the MSL improved by 0.93 minutes with CPAP.
Sangal and associates21 found an improvement in objec-
tive daytime sleepiness with the MWT but not the MSLT in
a group of sleepy patients undergoing treatment. Thus, a few
studies have suggested that the MWT might be more robust
Subjective and Objective Measures of Daytime Sleepiness 231
Mean number of inappropriate line crossings (ILC)
3 *
*
*
*
2
1
0
Very sleepy Sleepy Alert Controls
(019 min) (2033 min) (3440 min)
FIGURE 149 The mean number of inappropriate line crossings (ILCs) in four groups
of patients divided by the MWT sleep latency. The very sleepy and sleepy groups had
significantly more ILCs than the alert and control groups (*P < .05). From Philip P,
Sagaspe P, Taillard J, et al. Maintenance of wakefulness test, obstructive sleep apnea
syndrome and driving risk. Ann Neurol 2008;64:410416.
than the MSLT in documenting an improvement in sleepi-
of modafinil on daytime sleepiness in patients with narco-
lepsy, the sleep latency on both the MWT and the MSLT
400 mg daily.23 The increases in MSL were around 2 minutes
using both tests. However, of interest, the improvement at a
modafinil dose of 200 mg was significant only for the MWT.
The MSLT and MWT Assessment of Safety or Fit for Duty The MSL
on an MSLT or MWT required for a person to safely pursue
an occupation critically dependent on alertness has not been
standardized. Furthermore, the ability to stay awake is not
the same as maintaining alertness. Studies using driving
simulators have attempted to provide a performance-based
test of alertness.24,25 Test results showed decreased alertness
in patients with OSA and in patients with narcolepsy, as
compared with a control group. However, the simulator
results did not correlate with MSLT results, and in one study
half of each group performed as well as controls.24 A study
of untreated OSA patients found an MWT MSL less than 19
minutes was associated with impairment on a driving simu-
lator.25 The same group extended this work by testing patients
with OSA during actual 90-minute driving sessions on the
road with a driving instructor intervening if necessary (the
test car had two steering wheels).26 Inappropriate line cross-
ing was determined by video recording. Two groups very
sleepy with an MWT MSL less than 19 minutes and sleepy
with a MSL of 20 to 33 minutes had significantly higher line
crossings than controls and patients with mild sleepiness
(MWT MSL 3440 min) (Fig. 149).
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232 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness
Potential airplane pilots must undergo an aeromedical
examination (AME) by a Federal Aviation Administration
(FAA)designated medical examiner in order to receive a
medical certificate. If there is evidence of OSA, the patient
must be evaluated. If OSA is present, the disorder must be
adequately treated and a waiver is then needed to allow a
patient with OSA to obtain a medical certificate and fly
(Appendix 141). At the discretion of the examiner, an
MWT may be requested. However, the criterion for what
constitutes an acceptable MSL is not specified.
Limitations of MSLT and MWT Key points concerning the MSLT
and MWT and the limitations of the tests are outlined in
Box 146. Many factors can alter the MSL on the MSLT
including prior sleep deprivation and medications. Evalua-
tion of shift workers or patients with a delayed circadian
phase is problematic. The MSL by MSLT and the MSL by
MWT do not separate groups of normal individuals from
groups with sleep disorders causing EDS. Considerable
overlap in the MSL values occurs. If a patient is taking an
antidepressant that is known to suppress REM sleep, this
BOX 146
Key Points and Limitations of Multiple Sleep
Latency Test and Maintenance of Wakefulness Test
1. Proper interpretation of an MSLT requires analysis of the
preceding nocturnal sleep study, a careful medication
history, and knowledge of the sleep habits (diary) for at
least 1 wk preceding the MSLT.
2. Previous sleep deprivation (sleep restriction) can affect
the MSL.
3. No validated normal MSLT findings exist outside of the
usual testing hours of 0800 to 1800. Therefore,
evaluation of shift workers or patients with a delayed
circadian phase is problematic.
4. Due to large standard deviations, MSLs determined by
the MSLT and MWT do not separate normal populations
from those with sleep disorders such as narcolepsy.
5. MSLT diagnostic criteria are not validated for patients
younger than 8 years of age.
6. Antidepressants are widely used but are highly
problematic for MSLT.
7. As a diagnostic test for narcolepsy, the MSLT is specific if
OSA and other causes of SOREMPs are ruled out.
However, a significant percentage of false-negative
MSLTs can occur (sensitivity ~70%).
8. A small but clinically significant proportion of untreated
OSA patients can have 2 or more SOREMPs on the MSLT.
Therefore, if OSA is present, this should be adequately
treated before the MSLT can be used to support a
diagnosis of narcolepsy.
9. MWT results cannot be assumed to necessarily reflect a
patients ability to maintain alertness during real-life
conditions.
MSL = mean sleep latency; MSLT = multiple sleep latency test;
MWT = maintenance of wakefulness test; OSA = obstructive sleep apnea;
SOREMPs = sleep-onset rapid eye movement periods.
makes the MSLT interpretation problematic if fewer than 2
SOREMPs are noted. Conversely, discontinuation of antide-
pressant medication must be done cautiously. Weaning the
antidepressant is recommended rather than abrupt discon-
tinuation. Close patient follow-up and coordination of care
with the physician who prescribed the medication. In some
patients with severe depression, the risks may outweigh the
potential benefits. If patients have significant OSA, this dis-
order must be effectively treated (objective CPAP adherence
documented) before a MSLT evaluation to diagnose narco-
lepsy. Finally, a negative MSLT result does not rule out
narcolepsy and a significant proportion of patients with
narcolepsy and cataplexy may have a negative study on any
given day.12
CLINICAL REVIEW QUESTIONS
1. Which of the following are the MSLT diagnostic criteria
for narcolepsy?
A. MSL < 5 minutes and 2 or more SOREMPs in five
naps.
B. MSL < 8 minutes and 2 or more SOREMPs in five
naps.
C. MSL 8 minutes and 2 or more SOREMPs in five
naps.
D. MSL < 10 minutes and 2 or more SOREMPs in five
naps.
2. After the first epoch of sleep occurs, how many minutes
are recorded before the MSLT is terminated (beginning
with the start of the first epoch of sleep)?
A. 15 minutes of clock time.
B. 15 minutes of sleep.
C. Until the first epoch of unequivocal REM sleep.
D. 20 minutes of clock time.
3. After lights out, how many minutes of continuous wake
are allowed before an MSLT nap is terminated (maximum
sleep latency)?
A. 15 minutes.
B. 20 minutes.
C. 10 minutes.
D. 40 minutes.
4. Which of the following is true concerning the MWT?
A. A 20-minute test is recommended.
B. A PSG must precede testing.
C. A 40-minute test is recommended.
D. The patient is supine during testing.
5. Which of the following are true about the recommended
MSLT protocol?
A. PSG (required), patient out of bed between naps and
observed to prevent sleep (required).
B. Sleep diary for 1 to 2 weeks before MSLT (required).
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 Chapter 14
C. Urine drug screen (required).
D. Stop cigarette smoking 30 minutes before a nap
(optional).
6. About what percentage of normal individuals will have
an MSL 8 minutes?
A. 10%.
B. 20%.
C. 30%.
D. 40%.
7. An 18-year-old male is evaluated for daytime sleepiness.
He falls asleep in morning classes routinely but denies
cataplexy (emotionally induced muscle weakness). The
patients normal sleep period is from midnight (or later
on weekends) until approximately 6 am (weekdays) and
10 to 11 am on weekends. An MSLT is performed with
naps at 8 am, 10 am, 12 noon, 2 pm, and 4 pm. The
results include an MSL of 8 minutes and 2 SOREMPs (9
am and 11 am naps). The patient was off from school for
1 week before the sleep study. What is the most likely
diagnosis?
A. Narcolepsy without cataplexy.
B. Idiopathic hypersomnia.
C. Insufficient sleep syndrome.
D. Insufficient sleep syndrome and delayed sleep
phase.
8. A 20-year-old female pharmacy student is evaluated for
falling asleep in class. She also reports that when she
hears a very funny joke that her mouth drops open and
she has difficulty keeping her head upright. The patient
sleeps about 7.0 hours/night. The MSLT was preceded
by an unremarkable PSG. MSLT results include an MSL
of 5 minutes and 1 SOREMP in five naps. A urine drug
screen was declined. What is the most likely diagnosis?
A. Idiopathic hypersomnia.
B. Narcolepsy with cataplexy.
C. Insufficient sleep syndrome.
D. Occult drug abuse.
9. A 40-year-old policeman is evaluated for falling asleep
on the job. He denies cataplexy (emotionally induced
weakness). A PSG finds an AHI of 25/hr with many
obstructive apneas. An MSLT is performed and shows
an MSL of 4 minutes and 2 SOREMPs. What is the most
likely diagnosis?
A. Narcolepsy without cataplexy.
B. OSA.
C. OSA and narcolepsy.
D. Insufficient sleep syndrome.
10. A lawyer regularly flies an airplane for recreation on
the weekends. During an FAA medical evaluation,
a history of snoring was noted. Subsequently, a PSG
Subjective and Objective Measures of Daytime Sleepiness 233
showed moderate to severe OSA. After treatment with
CPAP, the patient remained somewhat sleepy and began
taking modafinil (alerting agent). To receive medical
clearance for a pilots license, a PSG (to document ade-
quate CPAP) with a subsequent MWT was ordered. The
PSG found an AHI of 3/hr on CPAP treatment. The
patient took his usual modafinil before the MWT and
the MSL on four naps was 40 minutes. What do you
recommend?
A. Medical clearance (assuming continued treatment
adherence).
B. Denial of medical clearance.
C. Increase modafinil dose and repeat MWT.
D. Objective download of CPAP use.
11. All of the following concerning the MWT protocol are
true EXCEPT:
A. The patient is seated upright in bed.
B. A preceding PSG is not required.
C. The MWT is stopped after 3 consecutive epochs of
stage N1 or any single epoch of any other stage of
sleep (N2, N3, R).
D. Four naps lasting up to 40 minutes is recommended
(40-min protocol).
E. The study is stopped after the first epoch of any stage
of sleep.
Answers
1. C.
2. A.
3. B.
4. C.
5. A. A urine drug screen and sleep diary for 1 to 2 weeks
preceding the MSLT are optional. The practice param-
eters stated that they may be helpful. However, most
sleep centers include a drug screen and sleep diary as
part of their MSLT protocol. Cigarette smoking should
stop 30 minutes before a nap (required, not optional).
The patients should be out of bed between naps.
6. C. 30%.
7. D. The fact that only the morning naps show SOREMPs
and the history of a delayed sleep phase suggest that the
SOREMPs are due to a circadian phase delay. The patient
likely was sleeping for 6 hours or less on week nights.
The MSL of 8 minutes likely was longer than expected
as the patient likely obtained more sleep when not
waking up early to attend school.
8. B. The MSLT had only 1 SOREMP. However, the MSLT
is only about 70% to 80% sensitive. The patient gives a
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234 Chapter 14 Subjective and Objective Measures of Daytime Sleepiness
history consistent with cataplexy and, therefore, likely
has narcolepsy with cataplexy. If cataplexy is present in a
patient with a normal neurologic examination, the MSLT
is considered confirmatory (see Chapter 24). Drug abuse
is an important consideration. On questioning, the
patient admitted to exposure to second-hand marijuana
smoke from her boyfriend. For this reason, she declined
a urine drug screen. The patient did have mildly insuf-
ficient sleep, but this is not uncommon in students.
9. B. About 6% of patients with untreated OSA will have
an MSLT meeting criteria for narcolepsy. Sleep apnea
should be treated before an MSLT is performed. If
daytime sleepiness persists on adequate treatment and
narcolepsy is suspected, a PSG on treatment (or after
surgical treatment) followed by an MSLT can be used to
support a diagnosis of narcolepsy (the patient has both
OSA and narcolepsy). Note that if the patient had
unequivocal cataplexy, then the correct answer is C
(both OSA and narcolepsy are present).
10. A and D? The use of an MWT to clear a patient for duty
where alertness is essential is an area of controversy. A
normal MWT does not ensure the patient will perform
safely (i.e., adhere to treatment and obtain adequate
sleep). The required sleep latency cutoff is poorly
defined. The use of a patients usual stimulant medica-
tion before the MWT seems reasonable but is not
included in the MWT practice parameters. In this case,
the patient maintained wakefulness during the entire
test. A CPAP download showed excellent adherence. A
recommendation for medical clearance was reported
with the stipulation that the patient demonstrate contin-
ued adherence to treatment.
11. E. Although the sleep latency is defined as the time
from lights out to the first epoch of any stage of sleep,
the study is terminated after 3 consecutive epochs of
stage N1 or a single epoch of any other stage of sleep
(N2, N3, R).
REFERENCES
1. Johns MW: A new method for measuring daytime sleepiness:
The Epworth Sleepiness Scale. Sleep 1991;14:540545.
2. Johns MW: Sleepiness in different situations measured by the
Epworth Sleepiness Scale. Sleep 1994;17:703710.
3. Gottlieb DJ, Whitney CW, Bonekat WH, et al: Relation of
sleepiness to respiratory disturbance index. Am J Respir Crit
Care Med 1999;159:502507.
4. Patel SR, White DP, Malhotra A, et al: Continuous positive
airway pressure therapy in a diverse population with obstruc-
tive sleep apnea. Arch Intern Med 2003;163:565571.
5. Benbadis SR, Mascha E, Perry MC, et al: Association between
the Epworth Sleepiness Scale and the multiple sleep latency test
in a clinical population. Ann Intern Med 1999;130:289292.
6. Sangal RB, Mitler MM, Sangal JM: Subjective sleepiness
ratings (Epworth Sleepiness Scale) do not reflect the same
parameter of sleepiness as objective sleepiness (maintenance
of wakefulness test) in patients with narcolepsy. Clin Neuro-
physiol 1999;110:21312135.
7. Richardson GS, Carskadon MA, Flagg W: Excessive daytime
sleepiness in man: multiple sleep latency measurements in nar-
coleptic and control subjects. Electroencephalogr Clin Neuro-
physiol 1978;45:621627.
8. Carskadon MA: Guidelines for the multiple sleep latency test.
Sleep 1986;9:519524.
9. Standards of Practice Committee, American Sleep Disorders
Association: The clinical use of the multiple sleep latency test.
Sleep 1992;15:268276.
10. Littner MR, Kushida C, Wise M, et al: Practice parameters for
clinical use of the multiple sleep latency test and the mainte-
nance of wakefulness test. Sleep 2005;28:113121.
11. Arand D, Bonnet M, Hurwitz T, et al: A review by the MSLT
and MWT Task Force of the Standards of Practice Committee
of the AASM. The clinical use of the MSLT and MWT. Sleep
2005;28:123144.
12. Aldrich MS, Chervin RD, Malow BA: Value of the multiple
sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep
1997;20:620629.
13. American Academy of Sleep Medicine: International Classifi-
cation of Sleep Disorders, 2nd ed. Diagnostic and Coding
Manual. Westchester, IL: American Academy of Sleep Medi-
cine, 2005, pp. 8190.
14. Janjua T, Samp T, Cramer-Bornemann MC, et al: Clinical
caveat: prior sleep deprivation can affect the MSLT for days.
Sleep Med 2003;4:6972.
15. Chervin RD, Aldrich MS: Sleep onset REM periods during
multiple sleep latency tests in patients evaluated for sleep
apnea. Am J Respir Crit Care Med 2000;161:426431.
16. Carskadon M: The second decade. In Gulleminault C (ed):
Sleeping and Waking DisordersIndications and Techniques.
Boston: Butterworths, 1982, pp. 99125.
17. Carskadon MA, Wolfson AR, Acebo C, et al: Adolescent sleep
patterns, circadian timing, and sleepiness at a transition to early
school days. Sleep 1998;21:871881.
18. Doghramji K, Mitler MM, Sangal RB, et al: A normative study
of the maintenance of wakefulness test (MWT). Electroen-
cephalogr Clin Neurophysiol 1997;103:554562.
19. Poceta JS, Timms RM, Jeong D, et al: Maintenance of wakeful-
ness test in obstructive sleep apnea syndrome. Chest
1992;101:893902.
20. Marshall NS, Barnes M, Travier N, et al: Continuous positive
airway pressure reduced daytime sleepiness in mild to moder-
ate obstructive sleep apnea: a meta-analysis. Thorax 2006;61:
430434.
21. Sangal RB, Thomas L, Mitler MM: Maintenance of wakefulness
test and multiple sleep latency test: measurements of different
abilities in patients with sleep disorders. Chest 1992;101:
898902.
22. Sangal RB, Thomas L, Mitler M: Disorders of excessive sleepi-
ness: treatment improves the ability to stay awake but does not
reduce sleepiness. Chest 1992;102:699703.
23. Randomized Trial of modafinil as a treatment for the excessive
daytime somnolence of narcolepsy: US Modafinil in Narcolepsy
Multicenter Study Group. Neurology 2000;54:11661175.
24. George CFP, Boudreau AC, Smiley A: Comparison of simu-
lated driving performance in narcolepsy and sleep apnea
patients. Sleep 1996;19:711717.
25. Sagaspe P, Taillard J, Chaumet G, et al: Maintenance of wakeful-
ness test as a predictor of driving performance in patients with
untreated obstructive sleep apnea. Sleep 2007;30:327330.
26. Philip P, Sagaspe P, Taillard J, et al: Maintenance of wakefulness
test, obstructive sleep apnea syndrome and driving risk. Ann
Neurol 2008;64:410416.
DaneshGroup.com

Federal Aviation Administration Policy
Concerning Fitness to Fly in Sleep Apnea Patients
Examiners may re-issue an airman medical certificate under
the provisions of an Authorization, if the applicant provides
the following:
An Authorization granted by the FAA; and
A current report (performed within last 90 days)
from the treating physician that references the present
treatment, whether this has eliminated any symptoms,
and with specific comments regarding daytime
sleepiness.
If there is any question about response to or compliance
with treatment, then a Maintenance of Wakefulness
Test (MWT) will be required.
The Aeromedical Examiner must defer to the Aerospace
Medical Certification Division (AMCD) or Region if:
Available at http://flightphysical.com/AASI/AASI-Sleep-Apnea.htm
Appendix 14-1
There is any question concerning the adequacy of
therapy;
The applicant appears to be non-compliant with
therapy;
The MWT demonstrates sleep deficiency; or
The applicant has developed some associated illness,
such as right-sided heart failure.
Authorization for Special Issuance of a Medical Certificate
(Authorization), valid for a specified period, may be granted
to a person who does not meet the established medical stan-
dards if the person shows to the satisfaction of the Federal
Air Surgeon that the duties authorized by the class of medical
certificate applied for can be performed without endangering
public safety during the period in which the Authorization
would be in force.
DaneshGroup.com
DaneshGroup.com

Obstructive Sleep Apnea
Syndromes: Definitions,
Epidemiology, Diagnosis,
and Variants
Chapter Points
Risk factors for the presence of OSA include obesity,
male gender, older age, and postmenopausal status
(not on HRT). Hypothyroidism, acromegaly, cigarette
smoking, and chronic alcohol use are also considered
risk factors but the evidence is less compelling.
A significant proportion of patients diagnosed with
OSA based on an increased AHI do not complain of
daytime sleepiness.
A high Mallampati (or modified Mallampati) score for
the upper airway is a predictor of the presence of OSA.
Patients with habitual snoring, witnessed apnea or
gasping, hypertension, and a large neck circumference
are at increased risk for having OSA.
Questionnaires are not sufficiently sensitive or specific
to obviate the need for objective testing to determine
the presence or absence of OSA.
In patients with milder OSA, the amount of supine and
REM sleep may have a large impact on the overall AHI.
The two groups of patients with OSA who have
daytime hypercapnia are those with the OHS and the
combination of obstructive airways disease (COPD)
and OSA.
Approximately 80% of patients with the OHS have
OSA. The other 20% have sleep-related worsening of
daytime hypercapnia and hypoxemia with relatively
few discrete apneas or hypopneas.
Patients with OSA and obstructive airway disease
(COPD) may have severe arterial oxygen desaturation
during sleep and daytime hypercapnia.
Pediatric patients with OSA often present with a
different symptom complex than that of adults.
Common manifestations include daytime hyperactivity,
Chapter 15
labored breathing during sleep, diaphoresis, and
paradoxical chest movement. Enuresis can also be a
manifestation of pediatric OSA.
The age range of highest prevalence of pediatric OSA
patients is typically from 2 to 8 years when
hypertrophy of the adenoids and tonsils occurs.
The values of respiratory indices considered to be
diagnostic of pediatric OSA vary but are typically an
obstructive AI > 1/hr or obstructive AHI > 12/hr. The
decision to treat is based on symptoms as well as PSG
findings.
HISTORY AND DEFINITIONS
The obstructive sleep apnea (OSA) syndrome was first rec-
ognized as a significant health problem only over the last
half of the 20th century. In 1956, Burwell and coworkers1
used the term pickwickian syndrome to describe individuals
with obesity, hypersomnolence, hypercapnia, cor pulmonale,
and erythrocytosis. The term pickwickian was based on
the character Fat Boy Joe from Charles Dickens The Posthu-
mous Papers of the Pickwick Club (1837), who was markedly
obese and tended to fall asleep uncontrollably during the
day. The current terminology describing such individuals is
the obesity hypoventilation syndrome (OHS). We now know
that such patients represent only 10% to 15% of the total
number of patients with OSA. Guilleminault and colleagues2
described the OSA syndrome in patients with daytime sleep-
iness and obstructive apneas on polysomnography (PSG).
An apnea index of 5/hr or greater was considered abnormal.3
An apnea was defined as absent airflow at the nose and
mouth for 10 seconds or more. Obstructive apneas are
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238 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
secondary to airway closure at a supraglottic location that
reverses at apnea termination often associated with a brief
awakening (arousal).4 Obstructive apneas are followed by a
fall in arterial oxygen saturation (SaO2) of varying severity.
It was soon realized the episodes of reduced airflow and tidal
volume (hypopneas) that are the result of upper airway nar-
rowing are also clinically significant.5,6 Patients with primar-
ily hypopneas had the same symptoms, arousals, and arterial
oxygen desaturation as patients with obstructive apneas. The
term obstructive sleep apnea hypopnea syndrome (OSAHS)
has been used to be more inclusive. However, many clini-
cians still use the term obstructive sleep apnea (OSA) to refer
to the syndrome and the term OSA is used in this chapter
with the understanding that patients may have variable
amount of apneas and hypopneas. As discussed in Chapter
8, the definition of hypopnea has varied considerably.7,8 The
American Academy of Sleep Medicine (AASM) scoring
manual9 recommends scoring apnea on the basis of an oro-
nasal thermal sensor and hypopnea on the basis of nasal
pressure monitoring. The recommended hypopnea defini-
tion requires a 30% reduction in nasal pressure signal for 10
seconds or longer in association with a 4% or greater arterial
oxygen desaturation. The alternative definition of hypopnea
requires a 50% or greater reduction in the nasal pressure
signal associated with either an arousal or a 3% or greater
arterial oxygen desaturation. Patients with OSA have vari-
able proportions of obstructive, mixed, and central apneas
as well as hypopneas.
Diagnostic Criteria
As discussed in Chapter 8, the apnea-hypopnea index (AHI)
is defined as the number of apneas and hypopneas per hour
of sleep. The respiratory disturbance index (RDI) is the
number of apneas, hypopneas, and respiratory effortrelated
arousals (RERAs) per hour of sleep (RDI = AHI + RERA
index). RERAs are events associated with increased respira-
tory effort (as evidenced by esophageal pressure manometry
or flattening of the nasal pressure signal) for 10 seconds or
longer that are associated with arousal but do not meet cri-
teria for hypopnea9 (see Chapter 8). Whereas the recent
AASM scoring manual defines RERAs, the manual does not
define the term RDI. The Centers for Medicare and Medicaid
Services (CMS) guidelines10 regarding reimbursement crite-
ria for continuous positive airway pressure (CPAP) define
the RDI as the number of respiratory events per hour of
monitoring time. This definition refers to the respiratory
event index obtained from portable monitoring (PM) devices
that do not record sleep. To add to the confusion, some
publications and sleep centers use the term RDI as the
number of apneas and hypopneas per hour of sleep. There-
fore, careful attention to the respiratory event definition is
required when reading the literature or a sleep study
interpretation.
A commonly used diagnostic criteria for OSA syndrome
has been an AHI 5/hr associated with symptoms or an
AHI 15/hr with or without associated symptoms.11,12 Some
BOX 151
International Classification of Sleep Disorders,
2nd Edition, Criteria for Obstructive Sleep Apnea
Diagnosis = A + B + D or C + D
A. At least one of the following applies:
i. Complaints of unintentional sleep episodes during
wakefulness, daytime sleepiness, unrefreshing sleep,
fatigue, or insomnia.
ii. Awakenings with breath-holding, gasping, or
choking.
iii. Bed partner reports loud snoring and/or breathing
interruptions during the patients sleep.
B. Polysomnography shows the following:
i. Scoreable respiratory events (apneas + hypopneas +
RERAs)/hr of sleep 5/hr.
ii. Evidence of respiratory effort during all or a portion
of each respiratory event (in the case of RERAs,
respiratory effort is best detected by esophageal
manometry).
OR
C. Polysomnography shows the following:
i. Scoreable respiratory events (apneas + hypopneas +
RERAs)/hr of sleep 15/hr.
ii. Evidence of respiratory effort during all or a portion of
each respiratory event.
D. The disorder is not better explained by another current
sleep disorder, medical or neurologic disorder, medica-
tion use, or substance use disorder.
RERAs = respiratory effortrelated arousal.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
diagnostic criteria have used the RDI ([apneas + hypopneas
+ RERAs]/hour of sleep) instead of the AHI. The Interna-
tional Classification of Sleep Disorders, 2nd edition (ICSD-
2), criteria for a diagnosis of the OSA syndrome in adults13
(Box 151) requires either scoreable respiratory events
(apneas, hypopneas, or RERAs) of 5/hr or greater with asso-
ciated symptoms or scoreable respiratory events of 15/hr or
greater with or without symptoms. Of note, the ICSD-2 cri-
teria mentions only scoreable respiratory events (apneas,
hypopneas, RERAs) per hour of sleep and does not define
the parameter RDI.
EPIDEMIOLOGY OF OSA
Prevalence and Progression
Prevalence is defined as the proportion of a population with
a condition. The prevalence of OSA depends on the defining
RDI or AHI criteria, the definition of hypopnea, the method
used to detect airflow, and presence or absence of a require-
ment that symptoms be present. The Wisconsin-based cohort
study of state employees younger than 65 years of age found
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 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
a prevalence of sleep-disordered breathing (SDB) defined as
an AHI of 5/hr or greater (with hypopneas based on a defini-
tion of discernible change in airflow and 4% desaturation)
to be 9% in women and 24% in men.14 The sleep apnea syn-
drome, defined as the presence of both SDB and self-reported
sleepiness, was present in 2% of women and 4% of men.
Bixler and associates15 found a 17% and 7% prevalence of an
AHI greater than 5/hr in and 15/hr in men, respectively.
Higher prevalence rates may be present in referral or clinical
populations. It is estimated that in Western countries, up to
5% of the population have an undiagnosed OSA syndrome
(elevated AHI and symptoms).16 Another publication in
1997 presented data that 93% of women and 82% of men
with moderate to severe OSA were undiagnosed.17 There is
also evidence that OSA severity can progress with time.
Analysis of 8-year follow-up of 282 participants of the Wis-
consin cohort study showed a mean increase in the AHI
from 2.6 events/hr to 5.1.16 In obese individuals with a body
mass index (BMI) over 30, the mean AHI increased from
4.8/hr to 10.1/hr. However, not all studies of untreated
patients with OSA have also shown progression in AHI
severity.
Risk Factors
A number of population-based studies have documented
several risk factors for the presence of OSA (Table 151).16
Of these, the most consistent findings have been the presence
of obesity and male gender.16,18
Obesity
An association between AHI and obesity has been docu-
mented in many studies.1621 Peppard and coworkers19 fol-
lowed the effects of weight change on AHI. A 10% weight
gain predicted an approximate 32% increase in the AHI. A
10% weight loss predicted a 26% reduction in the AHI. A
10% increase in weight was associated with a sixfold increase
TABLE 151
Risk Factors for Obstructive Sleep Apnea
RISK FACTOR EVIDENCE
Obesitypresent in roughly 70% +++
of OSA
Male sex +++
Aging ++
Postmenopausal state ++
Black race + (some studies)
Alcohol ++
Smoking + Postmenopausal Status
OSA = obstructive sleep apnea.
Adapted from Malhotra A, White DP: Obstructive sleep apnea. Lancet
2002;360:237245.
239
in the risk of developing moderate to severe OSA. Other
studies have documented a decrease in the AHI with weight
loss.22,23 Whether the type of obesity or areas of excess fat
(neck vs. abdomen) are important is currently under inves-
tigation. Davies and colleagues21 found that neck circumfer-
ence correlated with AHI better than general obesity.
Prediction models for OSA have used neck circumference as
a predictor.24 However, a recent study found neck circumfer-
ence to correlate best with AHI in women whereas abdomi-
nal girth correlated better in men.25
Male Sex
In the Wisconsin cohort study by Young and associates,14,16
men had about twice the incidence of the OSA syndrome
compared with women (4% vs. 2%) (AHI 5/hr + symp-
toms). Bixler and coworkers26 found the prevalence of OSA
defined as an AHI greater than 10/hr + symptoms to be 3.9%
in men and 1.2% in women (P = .0006). Analysis of the Sleep
Heart Health data also showed the risk of OSA in men was
greater (odds ratio 1.5).27 Further discussion of the effect of
gender on the pathophysiology of OSA is contained in
Chapter 16.
Age
The prevalence of OSA appears to be higher in the elderly
than in middle-aged populations. The prevalence of a chronic
nonfatal disease would increase as cases accumulate even if
the incidence (new cases/yr) was constant or declining.
Ancoli-Israel and colleagues28 studied 427 community-
dwelling elderly age 65 years or older using limited channel
ambulatory monitoring. A prevalence of OSA, defined as an
AHI greater than 10/hr, was found to be 62%. Here, hypop-
neas were based on changes in flow (based on two channels
of respiratory inductance plethysmography) independent of
changes in the SaO2 (no oximetry). This is a prevalence of
about three times that in middle-aged populations. There is
evidence from the Sleep Heart Health Study that the SDB
prevalence increases from age 40 to around 60.27 After that,
the prevalence appears to plateau (Fig. 151). In older adults,
the AHI may be less correlated with excessive sleepiness and
increased cardiovascular risk. Enright and coworkers29
studied a large group of subjects over age 65 with question-
naires and echocardiography, ultrasound of the carotids, and
an electrocardiogram. Snoring was very common but, inter-
estingly, reported snoring seemed to decrease after age 75.
Loud snoring, observed apneas, and daytime sleepiness were
not associated with hypertension or the prevalence of car-
diovascular disease. Conversely, decreased snoring reports
could be secondary to a lower frequency of having a bed
partner or hearing deficits in the elderly. It is possible that
the presence of OSA in the elderly population has different
implications.30
Conventional wisdom is that postmenopausal women have
a greater incidence of OSA than premenopausal women.
However, the confounders of increased age and often
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240 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
FIGURE 151 The prevalence of obstructive sleep apnea (OSA)
tends to increase with age but levels off after age 65 years. AHI =
apnea-hypopnea index. From Young T, Shahar E, Nieto FJ, et al:
Prevalence of an AHI 15, %
Predictors of sleep disordered breathing in community dwelling adults:
the Sleep Heart Health Study. Arch Intern Med 2002;162:895.
increased BMI in the postmenopausal group complicate the
analysis. An analysis of the Wisconsin cohort study of the
risk of having an AHI greater than 15 (adjusted for age and
body habitus) found an odds ratio of 3.5 for greater risk in
postmenopausal compared with premenopausal women.31
Another frequently quoted study found a greater risk but
included men in the control group.26 The Sleep Heart Health
Study analysis of women older than 50 years found that the
prevalence of an AHI greater than 15/hr in women on
hormone replacement therapy (HRT) was approximately
half that of the nonusers.32 There was a higher prevalence of
SDB in non-HRT users even when other factors such as age
and BMI were considered. The risk was especially high in the
50- to 59-year-old group. Thus, it appears that postmeno-
pausal women are at increased risk of developing OSA if they
are not on HRT treatment.
Ethnicity
One study found that OSA is more common in African
American than in white populations.33 However, this finding
was not present in another study that controlled for differ-
ences in age and BMI.27 An investigation by Redline and
associates34 found an increase in the risk of having OSA
greater in African Americans than in whites only for those
younger than age 25 years. Ip and coworkers35 found a similar
prevalence of OSA in a Chinese population as in whites. The
fact that OSA is common in Asian areas where obesity is
much less common has led to the hypothesis that craniofa-
cial characteristics of the Asian population might predispose
to OSA.36 Whereas increasing BMI was still associated with
an increased prevalence of OSA in the study of Chinese
patients, the association was not as strong as that typically
seen in white populations. The lack of obesity in Asian
patients should certainly not discourage evaluation for pos-
sible sleep apnea.
Smoking
Analysis of data for the Wisconsin sleep cohort data by
Wetter and colleagues37 found that current cigarette smokers
are at a greater risk for sleep apnea than never smokers.
30
25
20
15
10
0
35 45 55 65 75 85
Age, yr
Heavy smokers were at the greatest risk. Of interest, former
smokers did not have an increased risk. Therefore, smoking
cessation should be considered in all patients with OSA.
Alcohol Intake
Most studies of acute ingestion of alcohol in patients with
snoring or OSA have found an increase in the AHI.38,39
Alcohol does suppress REM sleep and, in this sense, could
reduce the longer events associated with REM sleep during
the early part of the night. However, more severe desatura-
tions and presumably longer events do occur in some patients
in the early portion of the night if bedtime alcohol is con-
sumed.38 Block and associates40 found effects of alcohol on
breathing in normal men but not women. Stradling and
coworkers20 found alcohol consumption to be associated
with the presence of OSA in a group of middle-aged men.
However, definite epidemiologic evidence for a worsening of
OSA with chronic alcohol consumptions is lacking. It seems
likely that consumption of alcohol (or abstinence from
alcohol) could significantly change the AHI in individual
patients. Alcohol could also prolong respiratory events. In a
study of the effect of alcohol on the arousal response to mask
occlusion in normal subjects, ethanol ingestion delayed the
time to arousal during nonrapid eye movement (NREM)
sleep.41 Most occlusions were preformed in the early part of
the night when the alcohol level would have been higher.
Considering the very common use of alcohol, relatively little
is known about its effects on breathing during sleep.
Hypothyroidism
Hypothyroidism has been thought to be associated with
sleep apnea.4244 However, there are no large cohort studies
evaluating the prevalence of sleep apnea in hypothyroid sub-
jects versus euthyroid patients. Pelttari and coworkers43
examined 26 patients with hypothyroidism and 188 euthy-
roid control subjects, finding that 50% of hypothyroid
patients and 29% of control subjects had significant respira-
tory events. If hypothyroidism is found in a patient with
OSA, continued effective treatment is indicated until restora-
tion of the euthyroid condition.44 Even then, one would need
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 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants 241

a sleep study to demonstrate that treatment of OSA was not TABLE 152
needed. Whereas some physicians order thyroid function Recommendations for Evaluation of General
tests on all OSA patients, this is not cost effective. Winkel- Medical Patients and Populations at High Risk for
man and colleagues45 reviewed the results of 255 consecutive Obstructive Sleep Apnea
patients suspected of having OSA in whom thyroid function
ROUTINE COMPREHENSIVE
studies were ordered. Hypothyroidism was present in only
HIGH-RISK QUESTIONS SLEEP
1.6% of patients and the frequency did not differ between
PATIENTS FOR AND EXAMINATION
those documented to have OSA and those who did not.
OSA OBSERVATIONS QUESTIONS
Thyroid testing is recommended only for high-risk groups
(women > 60 yr) and if there are clinical signs or symptoms Obesity Obesity? Witnessed apneas?
suggesting possible hypothyroidism.46 Postmenopausal (BMI > 30) Retrognathia? Snoring?
Congestive heart Daytime Gasping/choking
women with OSA or OSA patients without predisposing
failure sleepiness? at night?
OSA risk factors might warrant thyroid studies. The reason
Atrial fibrillation Snoring? Nonrefreshing
hypothyroidism exacerbates OSA is unclear and possibly Refractory Breathing sleep?
multifactorial. Upper airway muscle myopathy, narrowing of hypertension pauses? Total sleep
the upper airway by mucoprotein deposition in the tongue Type 2 diabetes Hypertension? amount?
(macroglossia), and abnormalities in ventilatory control are Nocturnal Sleep
possible mechanisms. arrhythmias fragmentation?
CVA Nocturia?
Acromegaly Pulmonary Morning
Growth hormone excess resulting in acromegaly is also asso- hypertension headaches?
ciated with sleep apnea. Grunstein and associates46 noted High-risk driving Decreased
populations concentration?
that 60% of unselected patients with acromegaly had sleep
Preoperative for Memory loss?
apnea. Weiss and coworkers47 found that 75% of a group
bariatric Decreased libido?
with acromegaly had OSA. Independent predictors of OSA surgery Irritability?
included increased activity of acromegaly (higher growth
BMI = body mass index; CVA = cerebrovascular accident; OSA = obstructive
hormone), older age, and an increased neck circumference. sleep apnea.
Potential pathophysiologic mechanisms of the association From Epstein LJ, Kristo D, Strollo PJ, et al: Clinical guideline for the evaluation,
between acromegaly and OSA include macroglossia and management and long-term care of obstructive sleep apnea in adults. J Clin
Sleep Med 2009;5:263276.
increased muscle mass of the upper airway. Patients with
acromegaly may have central as well as obstructive apnea.46
Therefore, alterations in ventilatory control may also play a
role. Patients with acromegaly without sleep apnea may also BOX 152
have daytime sleepiness as a direct manifestation of growth Common Symptoms and Manifestations of
hormone excess. The daytime sleepiness may improve after Obstructive Sleep Apnea
effective treatment of the acromegaly.48
Symptoms Nocturnal Behavior
Excessive daytime Loud habitual snoring
DIAGNOSIS OF OSA Choking, gasping during
sleepiness
Recent clinical guidelines for the evaluation, management, Nonrestorative sleep sleep
and long-term care of OSA in adults recommended that Frequent awakenings Breathing pauses/witnessed
high-risk populations for OSA be questioned in detail con- Morning headaches apnea
Dry mouth in the morning Body movements,
cerning symptoms of OSA.49 However, certain basic sleep
Personality change restlessness in bed
questions were recommended for all patients as part of a
Intellectual changes
general history and physical examination (Table 152). The Erectile dysfunction
comprehensive sleep examination questions the patient con- Nocturia
cerning the typical manifestations of OSA. A number of
populations with a high prevalence of OSA have been identi-
fied including patients with refractory hypertension, conges-
tive heart failure, and recent or past cerebrovascular accident or nonrestorative sleep (Box 152). Patients may also report
or transient ischemic attack (see Table 152). a progression of symptoms with recent weight gain or nasal
congestion. The Epworth Sleepiness Scale (ESS), a subjective
estimate of the propensity to doze off in eight situations, is
OSA Symptoms and Key Historical Points
often (but not invariably) increased (see Chapter 14). The
The patient or bed partner frequently reports excessive range of the scale is 0 to 24 with greater than 10 indicating
daytime sleepiness, loud habitual snoring, gasping/choking excessive daytime sleepiness.50 Data in Table 153 taken
or witnessed apnea, personality change, morning headache, from one of the first descriptions of the ESS show that the
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242 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
TABLE 153
Epworth Sleepiness Scale Scores in Mild,
Moderate, and Severe Obstructive Sleep Apnea
MEAN TOTAL
AHI NUMBER ESS
(MEAN OF (MEAN
SD) SUBJECTS SD)
Mild OSA 8.8 2.3 22 9.5 3.3
(AHI >
515)
Moderate 21.1 4.0 20 11.5 4.2
OSA (AHI
> 1530)
Severe OSA 49.5 9.6 13 16.0 4.4
(AHI > 30)
AHI = apnea-hypopnea index; ESS = Epworth Sleepiness Scale;
OSA = obstructive sleep apnea; SD = standard deviation.
From Johns MW: Daytime sleepiness, snoring, and obstructive sleep apnea. The
Epworth Sleepiness Scale. Chest 1993;103:3036.
score increases with severity of OSA (the AHI), but there was
a wide range of scores at any AHI range.50 Other studies have
confirmed that the correlation between the AHI and subjec-
tive or objective sleepiness, although statistically significant,
is low (correlation coefficient in the range of 0.40.5).51,52 The
wide variability in symptoms is likely due in part to different
individual susceptibility to sleep fragmentation or other
factors contributing to symptoms of daytime sleepiness
such as medications or reduced sleep time. A number of
population-based studies have found that a substantial per-
centage of patients with OSA do not report daytime sleepi-
ness, and the absence of sleepiness should not discourage a
further evaluation. However, patients with more severe OSA
do have, on average, greater daytime sleepiness (Fig. 152).
It is important to remember that two patients with the same
AHI can have vastly different degrees of daytime sleepiness
or arterial oxygen desaturation. Severe desaturation, even in
the absence of daytime sleepiness, could put the patient at
risk for a number of adverse cardiovascular consequences of
sleep apnea.
A number of investigations have studied the effect of
gender on presenting symptoms of OSA.5355 In general, men
and women report many of the same symptoms. However,
women may report more insomnia and less witnessed apnea.
Women with OSA are also more likely to complain of depres-
sion, morning headache, awakenings, and fatigue.55 It is
important to remember that patients with central sleep
apnea may present with many of the same symptoms as
OSA. Historical elements that may alert the clinician to
possible central apnea include congestive heart failure or
the use of potent narcotics. Patients with congestive heart
failure can have either OSA, Cheyne-Stokes breathing, or a
combination of OSA and central sleep apnea. Patients with
narcotics often have central apneas at baseline or when
10
Mean Epworth Sleepiness Scale
9
8
RANGE
OF ESS 7
416
6
5
520 5 5 to 15 15 to 30 30
Apnea  hypopnea index
FIGURE 152 Epworth Sleepiness Scale increases with worsening OSA severity as
823 measured by the apnea-hypopnea index. However, note that the mean value is lower
than expected given the severity of OSA. Note the relative mild daytime sleepiness even
with severe OSA. These results are from a population-based study. Sleep clinic
populations may manifest greater sleepiness. From Gottlieb DJ, Whitney CW, Bonekat
WH, et al: Relation of sleepiness to respiratory disturbance index. Am J Respir Crit Care Med
1999;159:502507.
BOX 153
Obstructive Sleep Apnea Physical Examination
Key Elements in Patients Suspected of Having
Obstructive Sleep Apnea
Increased BMI*
Presence of nasal obstruction
Increased Mallampati or modified Mallampati score*
High-arched palate (narrow airway)
Retrognathia
Increased neck circumference (>17 inches in men, >16
inches in women)
Evidence of right heart failure (JVD, pedal edema)
*Independent predictor of the presence of OSA.
BMI = body mass index; JVD = jugular venous distention; OSA = obstructive
sleep apnea.
From Nuckton TJ, Glidden DV, Brownder WS, Claman DM: Physical
examination: Mallampati score as an independent predictor of obstructive
sleep apnea. Sleep 2006;29:903908.
undergoing a positive airway pressure (PAP) titration (see
Chapter 21).
Physical Examination
The physical examination of patients with suspected OSA
should target abnormalities known to be associated with the
syndrome (Box 153). These include measurement of BMI
and systemic blood pressure as well as careful examination of
the nose, ears, and oropharynx.5658 Observation of the oro-
pharynx usually reveals a crowded upper airway and exami-
nation of the patients face in profile may reveal retrognathia
(Figs. 153 and 154). Measurement of neck circumference
and observation of signs of right heart failure may also be
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 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants 243

MALLAMPATI AIRWAY CLASSIFICATION

MODIFIED MALLAMPATI AIRWAY CLASSIFICATION

Class I Class II Class III Class IV

Soft palate and Soft palate and Soft palate Soft palate
entire uvula part of uvula base of not visible
visible visible uvula visible

FIGURE 153 Mallampati and modified Mallampati airway classification. In the Mallampati maneuver, patients are instructed not to emit sounds but to
open the mouth as wide as possible and protrude the tongue as far as possible. In the modified Mallampati, the patient is instructed to open the mouth
as wide as possible without emitting sounds. Mallampati reproduced from Friedman M, Tanyeri H, La Rosa M, et al: Clinical predictors of obstructive sleep
apnea. Laryngoscope 1999;109:19011907; and modified Mallampati reproduced with permission from Nuckton TJ, Glidden DV, Brownder WS, Claman DM:
Physical examination: Mallampati score as an independent predictor of obstructive sleep apnea. Sleep 2006;29:903908.

FIGURE 154 A patient with severe retrognathia on the left and orthognathia
(normal) on the right. From Friedman M, Tanyeri H, La Rosa M, et al: Clinical predictors
of obstructive sleep apnea. Laryngoscope 1999;109:19011907.

revealing. A neck size greater than 17 inches in men and 16
inches in women suggests the possibility of OSA. However,
a smaller neck circumference does not rule out OSA.
The Mallampati (MP) score of the upper airway was
developed to predict the risk of difficult endotracheal intuba-
tion (see Fig. 153). The patients oropharynx is examined
with tongue protruded. The modified Mallampati score
(MMP), also called the Friedman score,56 is similar but the
patient simply opens the mouth without saying ah or
tongue protrusion. Friedman and coworkers56 found that the
MMP, tonsil size, and BMI were reliable predictors of OSA.
Zonato and colleagues57 found a significant correlation
between the AHI and the MMP and BMI. Although retrog-
nathia (see Fig. 154) was not correlated with AHI, this
abnormality was more frequent in patients with severe OSA
as compared with snorers. Nuckton and associates58 analyzed
over 30 variables reflecting airway anatomy, body habitus,
symptoms, and medical history and found the MMP and MP
to be independent predictors of the presence and severity of
OSA. The variables associated with an increased risk of OSA
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244 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
in their study included increased neck circumference, wit-
nessed apnea, and hypertension.
Laboratory Testing in OSA
Laboratory testing in patients with OSA is usually not indi-
cated apart from routine health maintenance unless a par-
ticular problem such as hypothyroidism is suspected. In
patients with severe nocturnal hypoxemia, polycythemia
(increased hematocrit) may be present. An unexplained
elevation in the serum CO2 (composed primarily of HCO3)
on electrolyte testing is suggestive of chronic compensation
for hypercapnia (in the absence of evidence of causes of
metabolic alkalosis).59,60 Pulmonary function testing, chest
radiography, and arterial blood gas testing are indicated
in patients with a low awake SaO2 or suspected hypo-
ventilation to eliminate pulmonary causes of impaired gas
exchange.60
Prediction of the Presence of OSA
A number of clinical indices and questionnaires have been
developed to predict the presence of OSA based on symp-
toms, signs, and measurements. Although they have some
success, they are neither satisfactorily sensitive nor specific
enough to be a substitute for objective documentation of the
presence of OSA by a sleep study. An adaptation of a predic-
tion rule developed by Flemons and coworkers24,61 used an
adjusted neck circumference (Table 154) to classify patients
as low, moderate, or high probability. The population in
which the prediction value was developed was predomi-
nantly male, hypopneas were defined as a reduction in
airflow associated with a 3% or greater desaturation, and the
presence of OSA was defined by an AHI greater than 10/hr.
Netzer and colleagues62 studied the utility of the Berlin
Questionnaire (Appendix 151) to predict whether patients
were high or low risk for having OSA. The questionnaire
consists of three categories: category 1 concerns snoring and
witnessed apnea, category 2 concerns being sleepy/tired/
fatigued more than three or four times a week or nodding
TABLE 154
Prediction of Obstructive Sleep Apnea
NC = measure neck circumference (cm)
A. If hypertension present, +4
B. If habitual snoring present, +3
C. If gasping or choking present, +3
Adjusted neck circumference = NC + A + B + C
<43 cm (17 inches) low probability
4348 cm (1719 inches) moderate probability
>48 cm (19 inches) high probability
From Flemons WW: Obstructive sleep apnea. N Engl J Med 2002;347:498504.
off while driving a vehicle, and category 3 concerns the
presence of hypertension. After questionnaire completion,
patients were studied by PM. The Berlin Questionnaire iden-
tified patients with an AHI 5/hr (based on assignment to
the high-risk group) with a sensitivity of 0.86 and a specific-
ity of 0.77. The STOP-BANG (snoring, tired, observed apnea,
[blood] pressure, body mass index, age, neck circumference,
gender) Questionnaire is a screening tool (Appendix 152)
that has been used for preoperative evaluation to detect sleep
apnea. A study of 2467 patients found sensitivities of 84%,
92%, and 100% for AHI cutoffs of greater than 5/hr, greater
than 15/hr, and greater than 30/hr.63,64
Diagnostic Testing for Suspected Sleep Apnea
Attended PSG is the gold standard to determine whether
OSA is present and to classify the severity.65 Figure 155
presents an obstructive apnea during REM sleep. Box 154
lists the classic PSG findings in patients with OSA. The
abnormality in the sleep architecture varies with severity.
Patients with severe OSA usually have a high arousal index,
increased wake after sleep onset (WASO) and stage N1 sleep,
and decreases in stage N3 or stage R sleep. A typical classi-
fication of OSA severity based on the AHI (or RDI in some
sleep centers) is 5 to fewer than 15/hr mild, 15 to 30 moder-
ate, and greater than 30/hr severe OSA. Whereas the AHI
(RDI) is the most widely used index for classification of
severity, it is also important to characterize the severity of
arterial oxygen desaturation. A widely accepted standard for
the characterization of the severity of desaturation does not
exist. It is common to present the number of desaturations
(usually defined as a drop in the SaO2 > 4%), the lowest SaO2,
the average SaO2 at desaturation, and the time below various
saturations. For example, a commonly used metric is the
time at or below an SaO2 of 88%.
PSG can diagnose OSA either with an entire night of
monitoring or by the initial diagnostic portion of a split
(partial-night) study. The second part of the study is used as
a PAP titration. CMS formerly required a minimum of 2
hours of sleep (not monitoring) during the diagnostic
portion to qualify a patient for reimbursement of CPAP
treatment. Currently, if less than 2 hours of monitoring is
performed, the number of events to qualify the patient
should be the same as if 2 hours of sleep had been recorded.
For example, if an AHI of 15/hr qualifies a patient for CPAP
(symptoms not required) a total number of apneas and
hypopneas must equal 30 or more10 (Box 155).
Because the AHI is often higher in the supine position66,67
and during REM sleep,6870 presentation of the AHI for those
conditions in the sleep study report may be useful. The diag-
nosis of postural OSA is usually made when the AHI-supine
is greater than twice the AHI-nonsupine.
Some clinicians define REM-associated OSA as a normal
AHI during NREM sleep associated with an elevated AHI
during REM sleep. Other clinicians use the term to denote
patients with an AHI-REM/AHI-NREM greater than 2.
There is also an interaction between body position and sleep
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 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
EMG
L,R,leg
EMG
ECG
Airflow
RC
AB
Vsum
SpO2
91%
FIGURE 155 An obstructive apnea during rapid eye movement (REM) sleep. The longest respiratory event duration and most severe arterial oxygen desaturation are usually
during REM sleep (especially supine REM sleep). Note the slowing of the heart rate at the start of the apnea and speeding at apnea termination. Here Vsum is the sum of
rib cage (RC) and abdominal (AB) respiratory inductance plethysmograph bands. ECG = electrocardiogram; EMG = electromyogram; SpO2 = pulse oximetry.
stage. The AHI tends to be higher during supine than during
nonsupine REM sleep.69 Patients with a mild to moderate
overall AHI are more likely to have REM-related OSA. An
occasional patient with REM-related OSA may exhibit very
severe arterial oxygen desaturation and long apneas during
REM sleep but a relatively normal AHI-NREM. A study by
Kass and coworkers70 identified a group of patients with
overall AHI less than 10/hr but AHI-REM greater than 15/
hr who had objective evidence of daytime sleepiness. Other
studies have not demonstrated a relationship between the
AHI-REM and sleepiness.71,72 A recent large population-
based analysis of the Sleep Heart Health Study cohort found
a relationship between the AHI-NREM but not the AHI-REM
and daytime sleepiness.73 However, treatment decisions in an
individual patient with REM-related OSA should be indi-
vidualized. In patients with milder OSA, there can be con-
siderable night-to-night variability in the AHI. The best
advice is to treat the patient not the AHI. If a patient with
REM-related OSA is symptomatic and the overall AHI is 5/
hr or greater, it is reasonable to offer treatment. However,
245
Arousal
REMs
22 sec
Apnea
Paradoxical
motion
100%
74%
one should carefully consider other causes of daytime sleepi-
ness (narcolepsy, insufficient sleep). Conversely, if a patient
is completely asymptomatic with an overall AHI of 15/hr or
less, conservative therapy may suffice.
Cyclic variation in heart rate is typically noted during the
repeated episodes of obstructive events.74,75 The heart rate
slows at the start of the events and increases at event termi-
nation (Fig. 156). Often, the heart rate remains between 60
and 100 bpm. A standard part of most PSG reports is to
present the maximum and minimum heart rate along with
notations of abnormalities (premature ventricular contrac-
tions, atrial fibrillation, sinus pauses).
There are many formats for summarizing respiratory
event results of PSG in OSA patients. However, given the
importance of REM sleep and supine sleep, the AHI is often
presented for those situations (Table 155). Note that the
patient in Table 155 has a much higher AHI during supine
and REM sleep. It is also important to present the amount of
supine sleep (% of total sleep time supine) during the record-
ing period. The longest respiratory events and most severe
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246 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants

BOX 154 BOX 155

Polysomnographic Findings in Obstructive Excerpt from CMS Transmittal 96RNCD:
Sleep Apnea A Clarification of Apnea-Hypopnea Index
and Respiratory Disturbance Index for NCD
EEG FINDINGS
240.4 (CPAP)
Increased WASO and stage N1
Reduced stage N3 A positive test for obstructive sleep apnea (OSA) is estab-
lished if either of the following criteria using the apnea-
Reduced stage R (REM sleep)
hypopnea index (AHI) or respiratory disturbance index
Increased respiratory arousals
(RDI) are met:
RESPIRATORY FINDINGS AHI or RDI greater than or equal to 15 events per hour of
sleep or continuous monitoring, respectively, or
Snoring
AHI or RDI greater than or equal to 5 and less than or
Obstructive, mixed apneas, and central apneas
equal to 14 events per hour of sleep or continuous moni-
Obstructive hypopneas toring, respectively, with documented symptoms of
AHI: mild 5 to <15/hr, moderate 1530/hr, severe > 30/hr excessive daytime sleepiness, impaired cognition, mood
AHI supine > 2 AHI nonsupine postural OSA disorders or insomnia, or documented hypertension,
AHI REM > AHI NREM common ischemic heart disease, or history of stroke.
Apnea duration REM > NREM The AHI is equal to the average number of episodes of
ARTERIAL OXYGEN DESATURATION apnea and hypopnea per hour of sleep.
The RDI is equal to the average number of respiratory
Lowest SaO2 during REM sleep disturbances per hour of continuous monitoring.
Longest REM periods in the early morning hours typically If the AHI or RDI is calculated based on less than 2 hours
have the worst desaturation of continuous recorded sleep, the total number of
recorded events to calculate the AHI or RDI during sleep
CYCLIC VARIATION IN HEART RATE
testing is at least the number of events that would have
Slowing of heart rate at apnea onset and speeding at event been required in a 2-hour period.
termination RDI refers to home sleep testing.
AHI = apnea-hypopnea index; EEG = electroencephalogram; NREM = Available at https://www.cms.gov/transmittals/downloads/R96NCD.pdf
nonrapid eye movement; OSA = obstructive sleep apnea; REM = rapid eye
movement; SaO2 = arterial oxygen saturation; WASO = wake after sleep onset.

ECG

Heart
rate

Snore
Nasal pressure
Nasal-oral
thermal flow
Chest
Abdomen

SpO2

1 sec

FIGURE 156 The heart rate during an obstructive apnea. The heart rate signal is the output of the oximeter (a moving time average) that tends to lag behind the actual change
in heart rate. Changes in the heart rate can be noted by changes in the RR interval, which widens at apnea onset then narrows at apnea termination. ECG = electrocardiogram;
SpO2 = pulse oximetry.
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 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants 247

TABLE 155
Typical Presentation of Respiratory Events
TOTAL
TST (min) 360
NREM (min) 290
REM sleep (min) 70
% supine 16
TOTAL SUPINE NONSUPINE NREM REM
TST in condition 360 60 300 290 70
OA (#) 24 14 10 4 20
MA (#) 5 5 0 0 5
CA (#) 2 1 1 1 1
Hypopnea (#) 24 19 5 20 4
Total (#) 55 39 16 25 30
AHI (#/hr) 9.2 39.0 3.2 5.2 25.7
AHI = apnea-hypopnea index; CA = central apnea; MA = mixed apnea; NREM = nonrapid eye movement; OA = obstructive apnea; REM = rapid eye movement;
TST = total sleep time.

arterial oxygen desaturation typically occur during REM BOX 156

sleep in the second part of the night. Split- or partial-night Severity of Associated Arterial Oxygen
sleep studies (initial part diagnostic, second part PAP titra- Desaturation
tion) are frequently used in severe patients (by AHI).
FACTORS ASSOCIATED WITH SEVERE DESATURATION
However, because there is often minimal REM sleep during
the diagnostic portion, the severity of arterial oxygen desatu- Low awake SaO2
ration based on a split study may be dramatically underesti- Long apnea time (long apnea duration, short ventilatory
mated. A full night of diagnostic monitoring provides the period between apneas)
best estimate of the typical severity of arterial oxygen desatu- Low ERV (FRC RV)
ration. Chapter 16 discusses the pathophysiology of OSA and Low FRCobesity
the determinants of severity of desaturation. But briefly, a low High RVobstructive lung disease
baseline awake SaO2, long apnea time (long apnea duration GROUPS WITH SEVERE DESATURATION
with short intra-apnea ventilation), and a low expiratory
Severe obesity
reserve volume (ERV) are associated with more severe arte-
Obesity-hypoventilation syndrome
rial oxygen desaturation (Box 156).76 A recent large study of
OSA + COPD (overlap syndrome)
the Wisconsin cohort found that a higher BMI was associated
with more severe arterial oxygen desaturation independent COPD = chronic obstructive pulmonary disease; ERV = expiratory reserve
volume; FRC = functional residual capacity; OSA = obstructive sleep apnea;
of age, gender, sleeping position, baseline SaO2, and event RV = residual volume; SaO2 = arterial oxygen saturation.
duration.77 A higher BMI had a greater effect on desaturation
during REM than during NREM sleep. In addition, a fall in
tidal volume had a greater effect on arterial oxygen desatura-
tion when the BMI was higher. The predicted change in the not appear different between supine and nonsupine REM
SaO2 was also higher in the supine position than in the lateral sleep, although supine REM sleep is associated with the worse
position, in men than in women, and in smokers than in desaturation. Figure 157 illustrates the effects of various
nonsmokers. Another study found that obstructive events in apnea durations on desaturation.
the supine position tended to be longer, were associated with
more severe desaturation, and were more likely to be associ-
Portable Monitoring
ated with an arousal at event termination.66 Respiratory
events during REM sleep tend to be of longer duration and The use of PM, also known as home sleep testing (HST) or
associated with more significant arterial oxygen desaturation out of center sleep testing (OCST), is discussed in detail in
during REM sleep.68 Apnea duration during REM sleep does Chapter 13. PM is most appropriate when PSG is difficult
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248 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
FIGURE 157 Variable arterial oxygen desaturation in a patient
with severe OSA. Note as expected longer apnea resulted in more
severe arterial oxygen desaturation. SpO2 = pulse oximetry. From
Berry RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley &
Belfus, 2003, p. 86.
Airflow
SpO2
due to immobility or safety issues, when there is a delay in
obtaining a PSG due to access or availability and the clinical
situation is urgent, when there is a high probability of OSA,
when complicated co-morbidities are not present, and when
coexisting sleep disorders that may benefit from PSG are not
present.78 It should be remembered that the AHI derived
from testing without electroencephalogram (EEG) provides
a number of events per hour of monitoring time, not total
sleep time. For example, if PSG and PM both identify 100
events, the total sleep time is 6 hours, and the monitoring
time is 7 hours, then the AHI PSG = 100/6 and the AHI PM
= 100/7. Therefore, the AHI by PM will likely be less than by
PSG, even if similar numbers of respiratory events are
detected. There is also the concern for a false-negative PM
study. This phenomenon is more likely if the patient does not
sleep well during PM with the result that monitoring time
greatly exceeds total sleep time. If there is a high index of
suspicion for OSA but the PM is negative for OSA, a PSG
should be performed.78
VARIANTS OF SNORING AND OSA
Primary (Simple) Snoring
Whereas snoring is a cardinal symptom of OSA, not all
snorers have OSA. Simple or primary snoring is defined as
the presence of snoring without associated symptoms of
insomnia, daytime sleepiness, or sleep disruption (Box 15
7). Although a PSG is not necessary unless OSA is suspected,
the PSG characteristics of simple snoring would include evi-
dence of snoring on the PSG as detected by audio recording,
snore sensor, or vibration in the nasal pressure signal (or
technologist report of snoring) AND the absence of a sig-
nificant number of apneas, hypopneas, or RERAs. Sleep
architecture is usually normal.
Snoring may be defined as a vibratory, sonorous noise
made during inspiration and, less commonly, expiration.79 It
is associated with a vibration (fluttering) of the soft palate
and other pharyngeal structures. Snoring is difficult to
35 sec 48 sec 26 sec
82% 85%
75%
BOX 157
Snoring (Simple or Primary Snoring) (ICSD-2)
1. Audible snoring noises are reported by an observer.
2. The patient has no complaints of insomnia, excessive
daytime sleepiness, or sleep disruption that are
attributable to snoring.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
quantify but may be described on the basis of intensity or
vibratory qualities. It is associated with a narrowing of the
upper airway and evidence of airflow limitation. Any process
that narrows the upper airway, increases nasal resistance, or
decreases upper airway muscle tone typically worsens
snoring. Thus, nasal congestion, the supine posture, and
ethanol or hypnotics may have this effect. There is a definite
male predominance, although a considerable number of
women also snore. Simple snoring is common and tends to
increase with age. Some studies have suggested that up to
60% of men and 40% of women older than age 40 are habit-
ual snorers. Snoring can be detected with snore microphones
and high-frequency oscillations can sometimes be seen in
the nasal pressure signal if appropriate high-filter settings are
used (e.g., 100 Hz). Chapter 8 discusses methods to detect
snoring. Snoring may be associated with paradoxical breath-
ing and high esophageal pressure deflections. Snoring inten-
sity is loudest in slow wave sleep and softest in REM sleep.
A possible association between primary (simple) snoring
and cardiovascular disease is still debated. One problem with
many population studies that addressed this topic is that PSG
was not performed to rule out sleep apnea. A recent study
by Lee and associates80 found that heavy snoring (defined as
the presence of snoring for > 50% of the night) was associ-
ated with increased carotid atherosclerosis independent of
other risk factors such as nocturnal hypoxemia and OSA
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 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
severity. In addition, patients with heavy snoring are at risk
for developing OSA as they age or if significant weight gain
occurs.
Although not every snorer needs a sleep study, evaluation
is recommended if the patient has a moderate to high likeli-
hood of having OSA, is symptomatic, or if a surgical inter-
vention is being considered. A PSG is also needed before an
oral appliance is made for snoring to rule out significant
OSA.65 If significant sleep apnea is present, this may
change the treatment approach. If upper airway surgery or
an oral appliance is used for treatment, a sleep study post-
operatively or with the oral appliance in place is needed to
document treatment efficacy. Some surgical interventions
such as laser-assisted uvuloplasty (LAUP) are indicated for
treatment of snoring but not OSA.81 Surgical treatments for
snoring and OSA are discussed in detail in Chapter 18. Of
note, if the patient has unsuspected moderate to severe OSA,
then PAP is the treatment of choice.12,49
The treatment options for simple snoring are similar to
those for mild OSA. These include weight loss, the side
sleep position, treatment of nasal congestion, upper airway
surgery, an oral appliance, and avoidance of alcohol.
Although nasal CPAP is effective for snoring, this treatment
is usually reserved for patients with OSA.82 Chapter 20 pro-
vides an overview of treatments for snoring and OSA.
Upper Airway Resistance Syndrome
Guilleminault and coworkers83 identified a group of patients
who exhibited subjective and objective (multiple sleep
latency test [MSLT]) daytime sleepiness but did not have an
AHI of 5/hr or greater (thermal devices measured airflow).
The group was defined by having a respiratory arousal index
greater than 10/hr using esophageal pressure monitoring.
The respiratory arousal events were not associated with
desaturation or a change in thermal devicedetected airflow.
The symptom of sleepiness responded to CPAP treatment.
The mean arousal index of the group was 33/hr (range 16
52) and the mean maximally negative esophageal pressure
nadir was 37 cm H2O. There has been controversy as to
whether the upper airway resistance syndrome (UARS) is a
distinct entity or simply a milder form of OSA.84,85 The
ICSD-2 does not contain a separate diagnostic category for
UARS.
As discussed in Chapter 8, esophageal manometry and
nasal pressure monitoring each identify many (but not all)
of the same events. However, it is possible that use of esopha-
geal pressure monitoring would identify a few patients
missed by nasal pressure monitoring. For example, a patient
arousing easily might develop relatively high inspiratory
effort (esophageal pressure excursions) before airflow
changed significantly. If PSG is performed using nasal pres-
sure and if an RDI of 5/hr or greater (RDI = apneas + hypop-
neas + RERAs/hr of sleep) is used to define OSA, then most
patients who would meet criteria for UARS as defined previ-
ously would also be diagnosed as having OSA. Furthermore,
if the alternative definition of hypopnea is used (considers
249
arousals as well as desaturation), most RERAs will be classi-
fied as hypopneas.86,87
Obesity Hypoventilation Syndrome
Most patients with the OSA do not have daytime hypoventila-
tion. Two groups of OSA patients who do present with
hypoventilation include those with OHS and the overlap
syndrome (a combination of chronic obstructive pulmonary
disease [COPD] and OSA). Those obese patients (BMI >
30 kg/m2) with daytime hypoventilation (partial pressure of
carbon dioxide [PCO2] 45 mm Hg) that is not secondary
to lung disease or muscle weakness are said to have OHS (Box
158).8892 These patients were previously referred to as pick-
wickian. It is important to recognize whether a patient has
OHS as well as OSA because this group has a high incidence
of complications if not properly treated. Nowbar and col-
leagues90 studied the outcomes of obese patients admitted to
a medical service. Of those who had hypoventilation, the
18-month mortality was 23% compared with 9% in the group
with equivalent obesity but no hypoventilation. Of interest,
only 6% of the hypoventilation group received treatment for
the hypoventilation!
Diagnosis of OHS
The definitive diagnosis of hypoventilation requires an arte-
rial blood gas while awake with a PCO2 of 45 mm Hg or
greater. However, an arterial blood gas is rarely performed
on a morbidly obese patient with severe OSA unless they
have daytime hypoxemia or present with respiratory failure.
Fortunately, an elevated serum HCO3 (primarily HCO3) is a
very useful clue that a patient with OSA should be tested for
BOX 158
Obesity Hyperventilation Syndrome
Daytime PCO2 > 45 + BMI > 30 kg/m2 + no lung disease
Suspect OHS if HCO3 > 27 mEq/L (especially without
reason for metabolic alkalosis)
High mortality if untreated
8090% of OHS patients have OSA
Severe nocturnal desaturation
100% sleep-related hypoventilation (worsening of
daytime hypercapnia)
Cor pulmonalecommon
Treatment
CPAPdaytime PCO2 may improve, the addition of
oxygen may be needed
BPAPrecommended for moderate to severe
hypercapnia or persistent low SaO2 on CPAP
BPAP + oxygen
Tracheostomy + oxygenrepeated respiratory failure
and nonadherence to PAP
BMI = body mass index; BPAP = bilevel positive airway pressure; CPAP =
continuous positive airway pressure; OHS = obesity hyperventilation
syndrome; OSA = obstructive sleep apnea; PAP = positive airway pressure;
PCO2 = partial pressure of carbon dioxide.
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250 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
hypoventilation. The serum CO2 is included on routine meta-
bolic or electrolyte laboratory panels. The elevated HCO3 in
OHS patients represents renal compensation for chronic
respiratory acidosis (elevated arterial partial pressure of
carbon dioxide [PaCO2]). However, an elevated HCO3 could
also be due to metabolic alkalosis. Mokhlesi and associates59
found that 20% of 410 patients referred to a sleep center to
rule out OSA had OHS. In this study, only 3% of OHS patients
had an HCO3 less than 27 mEq/L but 50% of patients with
an HCO3 of 27 or greater had OHS. The authors concluded
that patients with both OSA and an HCO3 greater than
27 mEq/L should undergo arterial blood gas testing. Other
clues that OHS may be present include a borderline awake
SaO2 (9092%) or evidence of significant cor pulmonale.
Patients with the OHS are a heterogeneous group.89 The
causes of hypoventilation include nocturnal upper airway
obstruction (OSA), decreased respiratory system compli-
ance from obesity, and intrinsic or acquired abnormalities in
ventilatory drive.91 Patients with OHS have very increased
levels of leptin. This is a protein produced mainly by adipose
tissue that is a ventilatory stimulant and interacts with the
hypothalamus to inhibit eating. OHS patients are believed
to have leptin resistance or perhaps central leptin defi-
ciency.92 Most OHS patients will have OSA (8090%) and
severe arterial oxygen desaturation.88,92 However, up to 20%
of OHS patients have an AHI of 5/hr or less but exhibit both
daytime hypercapnia and severe sleep-related hypoventila-
tion and arterial oxygen desaturation. One study character-
ized the patients on the basis of their response to PAP
treatment.89 Some OHS patients could be adequately treated
with CPAP alone. Opening the upper airway with CPAP
during sleep restored adequate oxygenation. Others still had
hypoventilation despite the absence of apnea or hypopnea.
Some with persistent airflow limitation responded to higher
levels of CPAP (decreasing the upper airway resistance). Pre-
sumably, they could not compensate for a high upper airway
resistance even if apnea and hypopnea were not present.
Some patients required the addition of supplemental oxygen
along with CPAP.92,93 Another group of patients required
either nasal bilevel positive airway pressure (BPAP) or
mechanical ventilation with or without oxygen. The group
of OHS patients who manifest hypoventilation without sig-
nificant OSA are likely to have abnormal ventilatory control
or very decreased respiratory system compliance due to
massive obesity. The relative importance of OSA, abnormal
ventilatory control, and decreased respiratory system com-
pliance varies between individuals with OHS. Of note,
patients with severe OHS who are not treated or do not
comply with treatment have a high mortality.90,94
Treatment of OHS
Piper and coworkers95 performed a randomized trial that
compared CPAP and BPAP for treatment of patients with
OHS. Patients with significant residual desaturation (SaO2 <
80% for > 10 min) on a level of CPAP that eliminated
obstructive events, an acute rise in PCO2 greater than 10 mm
Hg during REM sleep, or an increase in PCO2 greater than
10 mm Hg in the morning compared with the afternoon
were excluded. An equivalent reduction in daytime PCO2
was noted at 3 months in patients randomized to CPAP or
BPAP. Adherence to the treatment modalities was also not
significantly different. In the BPAP group, the mean inspira-
tory positive airway pressure (IPAP) and expiratory positive
airway pressure (EPAP) levels used were 16 and 10 cm H2O,
respectively, and the spontaneous mode of BPAP was
employed. A few patients in both groups required supple-
mental oxygen in addition to PAP. As noted, the most severe
OHS patients were excluded from this study and were treated
with noninvasive positive-pressure ventilation (NPPV;
BPAP) outside of the study protocol.
OHS patients may require high levels of EPAP to prevent
obstructive apnea and this tends to limit the available range
of pressure support unless very high IPAP levels are used. In
a study of the effect of NPPV in OHS patients by Berger and
colleagues,89 EPAP values up to 14 cm H2O and IPAP values
up to 25 cm H2O were needed. The mean IPAP and EPAP
values were 18 and 8 cm H2O, respectively. OHS patients
may present with acute respiratory failure.96,97 The treatment
of choice is PAP (usually BPAP and oxygen). Very severe
patients may require temporary endotracheal intubation and
mechanical ventilation. Tracheostomy can be life-saving in
patients noncompliant with PAP treatment who have
repeated bouts of hypercapnic respiratory failure.
For stable chronic OHS patients, treatment with PAP may
reduce the daytime PCO2 as well as reduce apnea and hypop-
nea and nocturnal desaturation. Berthon-Jones and Sulli-
van98 showed chronic CPAP treatment of OSA patients with
daytime hypoventilation resulted in a leftward shift in the
ventilatory response to carbon dioxide (ventilation plotted
vs. PCO2) during the day without a change in slope (Fig.
158). The PCO2 set point is lowered and there is higher
ventilation at any given PCO2. A study by Mokhlesi and
associates99 found that the amount of improvement in the
daytime PCO2 is critically dependent on adherence. There
was considerable variability but the PCO2 dropped by about
3 mm Hg for every hour of nightly adherence and reached
a plateau with longer than 4.5 hours of use.
In summary, the treatment of OHS patients may require
CPAP or BPAP with or without the need for supplemental
oxygen. Although CPAP is often sufficient for some patients,
most clinicians would use BPAP if the hypoventilation is
moderate to severe. Adequate treatment can improve daytime
as well as nocturnal gas exchange and prevent apneas and
hypopneas. It is of interest that a fair number of OHS patients
do not complain of significant daytime sleepiness. OHS
patients may present with acute on chronic respiratory
failure. Moderate to severe OHS patients have a poor prog-
nosis if they do not receive appropriate treatment or are not
adherent to treatment.
Overlap Syndrome
Patients with the OSA and COPD may have daytime
hypoventilation and severe nocturnal oxygen desaturation.
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 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants 251

60 TABLE 156
90 days Differences Between Children and Adults with
Obstructive Sleep Apnea
CHILDREN ADULTS
CLINICAL FINDINGS
Minute ventilation (L/min)

Peak age Preschool (46 yr) 6070

40 Sex ratio M = F age < 13 yr M>F

M > F if older
children
Control included
Etiology Adenotonsillar Obesity/upper
hypertrophy airway
structural shape
Weight Variable: failure to Obese
20 thrive to obese
55 65 75
Alveolar CO2 tension (mmHg) Excessive daytime Less common Common
sleepiness
FIGURE 158 The ventilatory response to hypercapnia at baseline and after 90 days of
continuous positive airway pressure (CPAP) treatment in OSA patients with daytime Neurobehavioral Hyperactivity, Impaired vigilance
hypercapnia. The slope did not change but the curves shifted to lower alveolar partial developmental
pressure of carbon dioxide (PACO2) and the set point (baseline PACO2) decreased. From delay
Berthon-Jones M, Sullivan CE: Time course of change in ventilatory response to CO2 with POLYSOMNOGRAPHY
long-term CPAP therapy for obstructive sleep apnea. Am Rev Respir Dis 1987;135:
144147. Definition of Any obstructive AHI 5/hr
abnormal apnea
OAHI > 1.01.4
Obstruction Obstructive Obstructive
pattern hypoventilation apnea/
An epidemiologic study found that patients with mild COPD Apnea during hypopnea
have no higher incidence of OSA than the general popula- REM sleep Higher AHI in REM
tion.100 However, because both COPD and OSA are common, sleep
the combination is common even if by chance. Of interest, Sleep architecture Normal Reduced stages
those patients with both airway obstruction and sleep apnea N3 and R
in this study had worsened arterial oxygen desaturation. Sleep stage with REM REM > NREM
An early study of a group of patients with OSA and hypo- OSA
ventilation found that the presence of COPD was associated
Cortical arousal Low rates < 50% High rates
with hypoventilation.101 Of note, patients with COPD alone
of apneas 6080% of apnea/
rarely retain CO2 until the forced expiratory volume in 1 hypopnea
second (FEV1) is below 1.0 L or 40% of predicted. However,
AHI = apnea-hypopnea index; NREM = nonrapid eye movement; OAHI =
patients with OSA and mild to moderate COPD may retain obstructive apnea-hypopnea index; OSA = obstructive sleep apnea;
CO2.101,102 Patients with the overlap syndrome tend to have REM = rapid eye movement.
particularly severe arterial oxygen desaturation at night.
They are often assumed to simply have COPD and are treated
with nocturnal oxygen alone. This may incompletely reverse
the nocturnal hypoxemia and worsen the CO2 retention
PEDIATRIC OSA
during sleep.103 The long-term outcome of patients with
the overlap syndrome may worsen if upper airway obstruc- The major differences in the presentation and characteristics
tion is not addressed.104 Proper treatment usually requires of OSA between children and adults are listed in Table 15
CPAP or BPAP and supplemental oxygen if needed.104,105 6.106110 Although very obese children or those with struc-
The daytime PCO2 may improve in some patients with ade- tural upper airway abnormalities can present with symptoms
quate treatment of upper airway obstruction during sleep. similar to those of adults, the typical history in childhood
Aggressive treatment of the underlying COPD with smoking OSA is one of hyperactivity or developmental delay111 com-
cessation and bronchodilators may also be helpful in improv- bined with abnormal sleep behaviors observed by the parents.
ing gas exchange both during the day and at night. More These nocturnal behaviors include snoring, labored breath-
information about the overlap syndrome is contained in ing, diaphoresis, paradoxical chest movement, or frequent
Chapter 22. movements during sleep. Pediatric patients may also have
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252 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants
enuresis as a manifestation of OSA. Barone and associates,112
using a case-controlled study, found obesity and enuresis to
be associated with sleep apnea but not with each other.
Epidemiology of Pediatric OSA
A 2008 review concluded that the prevalence of always
snoring in children ranged from 1.5% to 6%.108 Reports of
habitual snoring ranged from 5% to 12%. The prevalence
of parent-reported apneic events ranged from 0.2% to 4%.
Using questionnaires filled out by parents, the prevalence of
OSA has been estimated to be 4% to 11%. The prevalence by
diagnostic studies has been estimated to be 1% to 4%
(reported range 0.113%). Evidence suggests that pediatric
OSA is more common among children who are heavier.
Studies considering younger children (<13 yr) have gener-
ally found an equal prevalence of OSA in boys and girls. In
a majority of studies including older children, a male pre-
dominance was found.108 There may be a higher prevalence
among African Americans compared with whites. The age
range in which pediatric OSA is most common is said to be
from 4 to 6 years (or 2 to 8 according to some authors).106,108
This is the time that hypertrophy of the tonsils occurs.
Although pediatric patients with OSA typically present
with complaints of hyperactivity and behavioral problems
rather than daytime sleepiness, the presence of daytime
sleepiness may be greater than previously appreciated.113,114
First, pediatric patients in the age range for adenotonsillar
hypertrophy rarely self-report sleepiness. Questionnaires
have been developed to assess parental report of their chil-
drens sleepiness. However, parental report likely underesti-
mates objective daytime sleepiness. Obesity also appears to
affect the likelihood of pediatric OSA being associated with
objective sleepiness. Gozal and Kheirandish-Gozal114 found
that obese children tended to be more sleepy (based on a
MSLT mean sleep latency [MSL] 12 min) at any given
level of OSA. Of interest, in over 50% of cases with docu-
mented objective sleepiness, the parents did not report
excessive daytime sleepiness.
Diagnosis
The ICSD-2 criteria13 for the diagnosis of pediatric OSA are
listed in Box 159. The criteria emphasize parental observa-
tions as well as PSG findings. In pediatric sleep monitoring,
any scoreable obstructive apnea of a duration equal to two
respiratory cycles is considered abnormal. Many pediatric
sleep reports separate the central from obstructive apnea-
hypopnea index (OAHI). The values of the obstructive apnea
index (OAI; obstructive apneas/hr of sleep) or OAHI needed
to diagnose pediatric OSA remains somewhat controversial.
Table 157 presents normative values from two publications.
Most clinicians make the diagnosis of pediatric OSA based
on an obstructive apnea index (OAI) greater than 1/hr or an
OAHI greater than 1 to 2/hr. However, the decision to treat
a given patient depends on symptoms. No widely accepted
severity ranges are available, but many centers treat patients
BOX 159
Diagnostic Criteria for the Pediatric Obstructive
Sleep Apnea Syndrome (ICSD-2)
A. The caregiver reports snoring, labored/obstructed breath-
ing, or both during the childs sleep
B. The caregiver of the child reports observing at least one
of the following:
i. Paradoxical inward rib cage motion during
inspiration
ii. Movement arousals
iii. Diaphoresis
iv. Neck hyperextension during sleep
v. Excessive daytime sleepiness, hyperactivity, or
aggressive behavior
vi. Slow rate of growth
vii. Morning headaches
viii. Secondary enuresis
C. Polysomnography recording demonstrates one or more
scoreable respiratory events per hour (i.e., apnea or
hypopnea of at least two respiratory cycles in duration)
D. Polysomnography recording demonstrates either i or ii
i. At least one of the following is observed:
a. Frequent arousals from sleep associated with
increased respiratory effort
b. Arterial oxygen desaturation in association with the
apneic episodes
c. Hypercapnia during sleep
d. Markedly negative esophageal pressure swings
ii. Periods of hypercapnia, desaturation, or hypercapnia
with desaturation during sleep associated with snoring,
paradoxical inward rib cage motion during inspiration,
and at least one of the following:
a. Frequent arousals from sleep
b. Markedly negative esophageal pressure swings
E. The disorder is not better explained by another current
sleep disorder, medical or neurologic disorder, media-
tion use, or substance use disorder
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
with an OAHI of 2 to 5/hr. An AHI of 10/hr is considered
moderate to severe in children. Most apnea in pediatric
patients occurs during REM sleep. However, the most
common pattern in pediatric sleep monitoring is obstruc-
tive hypoventilation (Fig. 159). This pattern consists of
long periods of airflow limitation, increased inspiratory
effort, increased end-tidal partial pressure of carbon dioxide
(PETCO2), and variable amounts of arterial oxygen desatura-
tion. Traditional monitoring (thermistor flow) often demon-
strates few changes except for an elevation in PETCO2 and
perhaps no or mild drops in the SaO2. Paradoxical motion
of the chest and abdomen may be noted (chest moving
inward during inspiration). Nasal pressure monitoring shows
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 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants 253

TABLE 157 airflow limitation (flattening) and reduced but stable flow.
Normative Respiratory Values for Children Ages This common pattern is the reason that PETCO2 is an integral
1 to 18 part of most pediatric sleep studies. The AASM scoring
manual states that sleep-related hypoventilation in children
BECK AND
should be scored when the PCO2 > 50 mm Hg for 25% of
VALUE MARCUS* ULIEL ET AL
the total sleep time using transcutaneous or end-tidal mea-
Obstructive AHI 1.4 surement of the PCO2.9 However, a PSG study of normal
(#/hr) children by Uliel and coworkers115 recommended that
Obstructive AI 0 1 PETCO2 greater than 45 mm Hg for longer than 10% of total
(#/hr) (any obstructive sleep time be considered abnormal.
apnea is Although the major cause of OSA in children is adeno-
considered tonsillar hypertrophy, tonsil size does not correlate with find-
abnormal) ings on sleep studies. One child with large tonsils may be
Central apnea 0.4 0.9 without symptoms while another with modest tonsil enlarge-
index (#/hr) ment may have significant symptoms. Other upper airway
Time with SaO2 0% TST < SaO2 0% TST < SaO2
characteristics are likely responsible. With the obesity epi-
< 89 or 90% of 90% of 89% demic in children, obesity is becoming a major risk factor
(%TST) for OSA in children. Indeed, very obese children may present
with symptoms similar to those of adults (daytime
SaO2 nadir 91% 89
sleepiness).
Baseline sleeping
Tonsillectomy and adenoidectomy (TNA) is considered
SaO2 > 92%
the treatment of choice in patients with pediatric sleep apnea
Time PETCO2 <25% (even if obese). A PSG is recommended before TNA to avoid
50 mm Hg unnecessary surgery and to triage patients to appropriate
Time PETCO2 > <10% postsurgical care. Patients with a high AHI, extremes of body
45 mm Hg weight, severe oxygen desaturation, cor pulmonale, daytime
Periodic limb 4.3
hypoventilation, young age, and congenital craniofacial
movement abnormalities are at an increased risk for postoperative com-
index (#/hr) plications. In high-risk patients, TNA should be performed
AHI = apnea-hypopnea index; AI = apnea index; PETCO2 = end-tidal carbon
in the hospital with appropriate postoperative monitor-
dioxide pressure; SaO2 = arterial oxygen saturation; TST = total sleep time. ing.105,116 The efficacy of TNA is much lower than expected
*Beck SE, Marcus SL: Pediatric polysomnography. Sleep Med Clin and a postoperative PSG is recommended.117,118 Even if TNA
2009;4:393406.

Uliel S, Tauman R, Greenfield M, et al: Normal polysomnography respiratory

is initially successful, symptoms of OSA can recur in later
values in children and adolescents. Chest 2004;125:872878. life. The surgical treatment of OSA in pediatric patients is

Snore
Nasal
pressure
NO therm

Chest
Abdomen

SpO2
93%

Exhaled 50
PCO2 0

FIGURE 159 Obstructive hypoventilation in a pediatric patient with OSA. The end-tidal partial pressure of carbon dioxide (PCO2) is greater than 50 mm Hg and

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there is evidence of flattening of the nasal pressure (airflow limitation). A very mild drop in the pulse oximetry (SpO2) is noted.
254 Chapter 15 Obstructive Sleep Apnea Syndromes: Definitions, Epidemiology, Diagnosis, and Variants

discussed in more detail in Chapter 20. Patients with
significant residual OSA following TNA can be treated
with weight loss, CPAP, or other surgical procedures.
CLINICAL REVIEW QUESTIONS
1. Of the following, what is the best documented risk factor
for OSA?
A. Cigarette smoking.
B. Alcohol consumption.
C. Postmenopausal status.
D. Obesity.
2. Which of the following is NOT always true about patients
with the OHS?
A. Daytime PCO2 45 mm Hg.
B. BMI > 30 kg/m2.
C. Worsening PCO2 and PO2 with sleep.
D. AHI 5/hr.
3. Which of the following symptoms is less typical of pedi-
atric patients with OSA?
A. Diaphoresis and labored breathing during sleep.
B. Hyperactivity or behavioral problems.
C. Adenotonsillar hypertrophy of variable severity.
D. Daytime sleepiness.
4. Which of the following is the ICSD-2 criterion for diag-
nosis of OSA in adults?
A. (Apneas + hypopneas + RERAs)/hr = 5/hr.
B. (Apneas + hypopneas + RERAs)/hr = 15/hr.
C. (Apneas + hypopneas + RERAs)/hr = 5/hr +
symptoms
D. (Apneas + hypopneas + RERAs)/hr = 5/hr + symp-
toms OR (Apneas + hypopneas + RERAs)/hr 15/hr.
5. Which of the following group of symptoms in a patient
would indicate a good candidate for portable
monitoring?
A. Snoring, witnessed apnea, daytime sleepiness,
hypertension.
B. Snoring, witnessed apnea, congestive heart failure,
daytime sleepiness.
C. Snoring, no witnessed apnea, nonrestorative sleep, no
daytime sleepiness.
D. Snoring, daytime sleepiness, neuromuscular
disorder.
6. What is the approximate prevalence of OSA defined as an
AHI 5/hr associated with symptoms?
A. Men 10% Women 5%
B. Men 4% Women 2%
C. Men 2% Women 1%
D. Men 4% Women 4%
7. Which of the following combinations has the highest
probability of having OSA?
A. Snoring, no witnessed apnea, hypertension.
B. Snoring, daytime sleepiness, no witnessed apnea.
C. Snoring, witnessed apnea, hypertension.
D. No snoring, no witnessed apnea, daytime sleepiness.
Answers
1. D. Obesity is the best documented risk factor of those
listed.
2. D. Approximately 20% of OHS patients do not have OSA
but simply have daytime hypoventilation that worsens
during sleep.
3. D. Daytime sleepiness is not a major complaint of pedi-
atric OSA patients. However, sleepiness may not be rec-
ognized. Obese pediatric OSA patients are more likely to
report sleepiness.
4. D. This option most completely describes the criteria for
adult OSA.
5. A. This describes a patient with a high probability of
moderate to severe OSA who does not have co-morbid
medical disorder such as congestive heart failure or a
neuromuscular disorder. Patient C may well have sleep
apnea but is not considered to have a high probability of
having OSA based on lack of witnessed apnea.
6. B. This answer describes the findings of the Wisconsin
study by Young and associates. The prevalence likely
varies with the population being studied and the preva-
lence may well be increasing owing to the obesity
epidemic.
7. C. Snoring, witnessed apnea, and hypertension were
found to be major risk factors for the presence of OSA.
Although daytime sleepiness is a cardinal symptom of
OSA, many OSA patients do not report sleepiness.
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 Appendix 15-1

Berlin Questionnaire

Please choose the correct response to each question. c. 12 times/wk

d. 12 times/mo
Category 1 e. Never or nearly never
1. Do you snore? 8. Have you ever nodded off or fallen asleep while driving a
a. Yes* vehicle?
b. No a. Yes*
c. Dont know b. No

If you snore: If yes:

2. Your snoring is: 9. How often does this occur?
a. Slightly louder than breathing a. Nearly every day
b. As loud as talking b. 34 times/wk
c. Louder than talking* c. 12 times/wk
d. Very loudcan be heard in adjacent rooms* d. 12 times/mo
3. How often do you snore?
a. Nearly every day* Category 3: Somnolence
b. 34 times/wk* One or more of the following are present:
c. 12 times/wk a. Frequent somnolence or fatigue despite adequate
d. 12 times/mo sleep
e. Never or nearly never b. Falls asleep easily in a nonstimulating environment
4. Has your snoring ever bothered other people? (e.g., watching TV, reading, riding in or driving a car)
a. Yes* despite adequate sleep
b. No c. [Parent or teacher comments that child appears sleepy
c. Dont know during the day, is easily distracted, is overly aggressive,
or has difficulty concentrating]
5. Has anyone noticed that you quit breathing during your d. [Child often difficult to arouse at usual awakening
sleep? time]
a. Nearly every day*
b. 34 times/wk* Scoring:
c. 12 times/wk
If two or more items in category 1 are positive, category 1 is
d. 12 times/mo
positive.
e. Never or nearly never
If two or more items in category 2 are positive, category 2 is
positive.
Category 2
If one or more items in category 3 are positive, category 3 is
6. How often do you feel tired or fatigued after your sleep? positive.
a. Nearly every day* High risk of OSA: Two or more categories scored as
b. 34 times/wk* positive.
c. 12 times/wk Low risk of OSA: Only one or no category positive.
d. 12 times/mo
e. Never or nearly never
7. During your waking time, do you feel tired, fatigued, or
not up to par? *Items are considered positive.
a. Nearly every day*
Pediatric questions.
b. 34 times/wk*
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OSA = obstructive sleep apnea.

259
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 Appendix 15-2

STOP-BANG Scoring Model

1. Snoring 6. Age
Do you snore loudly (louder than talking or loud enough to Age older than 50 yr old? Yes No
be heard through closed doors)? Yes No
7. Neck circumference
2. Tired Neck circumference > 40 cm? Yes No
Do you often feel tired, fatigued, or sleepy during daytime?
8. Gender
Yes No
Gender male? Yes No
3. Observed
High risk of OSA: Answering yes to three or more items.
Has anyone observed you stop breathing during your sleep?
Low risk of OSA: Answering yes to less than three items.
Yes No
4. Blood pressure
Do you have or are you being treated for high blood pres-
sure? Yes No
5. BMI
BMI > 35 kg/m2? Yes No

BMI = body mass index; OSA = obstructive sleep apnea.

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Pathophysiology of Obstructive
Sleep Apnea
Chapter Points
Patients with OSA have a positive critical pressure
during sleep. A positive intraluminal pressure is
needed to keep the airway patent.
Patients with OSA have airway occlusion or severe
narrowing during sleep because of a variable
combination of factors including unfavorable upper
airway anatomy, inadequate upper airway muscle
compensation, and instability in ventilatory control.
Whereas a high arousal threshold may prolong
respiratory events, a low arousal threshold may
predispose to instability in ventilatory control.
Traits Contributing to Obstructive Sleep Apnea
ANATOMIC/
PHYSIOLOGIC TRAIT APNEA PREDISPOSITION
Upper airway anatomy Small pharyngeal airway
Upper airway motor Poor muscle response
control during sleep
Ventilatory control stability High loop gain
Arousal threshold Low arousal threshold
From White DP: The pathogenesis of obstructive sleep apnea. Am J Respir
Cell Mol Biol 2006;34:16.
The reasons for the greater prevalence of OSA in men
than in women are incompletely understood. Men
have longer upper airways and this may predispose to
upper airway collapse.
The activity of phasic upper airway muscles (e.g.,
genioglossustongue protruder) increases with each
inspiration. The activity of tonic upper airway muscles
is constant (does not vary with respiration). However,
the activity level of tonic muscles can vary with sleep
state (wake > NREM > REM). The activity of phasic
upper airway muscles is controlled by central pattern
generators, sleep state (wakefulness stimuli, NREM,
REM), and negative-pressure stimulation of upper
airway mechanoreceptors. More negative upper airway
Chapter 16
pressure is associated with increased upper airway
inspiratory activity in the genioglossus.
Upper airway muscle activity falls with sleep onset and
the decrease is greater in patients with OSA than in
normal individuals. During wake, increased upper
airway muscle activity in patients with OSA may
compensate for unfavorable anatomy.
The arousal stimulus during obstructive apnea and
hypopnea appears to be proportional to the
magnitude of inspiratory effort (esophageal pressure
excursions). Hypercapnia and hypoxemia may cause
increasing respiratory effort, but arousal occurs when
the level of effort reaches an arousal threshold.
The arousal threshold to respiratory stimuli during
NREM sleep is increased in patients with OSA
compared with normal individuals (higher inspiratory
effort is needed to trigger arousal).
Factors associated with more severe arterial oxygen
desaturation include a higher BMI, low awake SaO2 or
PaO2, longer respiratory events/shorter period of
ventilation between events, and a smaller ERV.
PATHOGENESIS OF UPPER
AIRWAY OBSTRUCTION
Multiple factors determine upper airway patency during
sleep (Table 161).19 Different factors may be more or less
important in a given individual. Patients with obstructive
sleep apnea (OSA) tend to have small upper airways either
secondary to a small bony enclosure or due to increased soft
tissue surrounding the airway.10,11 In general, a short and
posteriorly placed mandible, a long dependent palate, a large
tongue, nasal obstruction, and thick lateral pharyngeal walls,
and/or pharyngeal fat all predispose to upper airway collapse
during sleep. Most studies have suggested that the shape of
the upper airways of OSA patients differs from that of normal
individuals and is narrower in the lateral dimension.1012 A
study comparing the passive properties of the upper airway
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264 Chapter 16 Pathophysiology of Obstructive Sleep Apnea

during general anesthesia in normal individuals with those during inspiration is commonly caused by narrowing of a
of OSA patients found that the upper airways of OSA patients hypotonic upper airway in response to the increasingly nega-
are narrower and more collapsible.13 tive intraluminal pressure developed during inspiration.14,15
Airflow through the pharynx shows various degrees of In Figure 162, the first three breaths do not show airflow
airflow limitation during sleep. Inspiratory flow limitation is limitation and airflow has a round shape. The fourth breath,
defined by an increase in the pressure drop across the which occurs after sleep onset, demonstrates airflow limita-
upper airway (more negative supraglottic and intrathoracic tion with a constant flow during the time when the inspira-
pressure) without a corresponding increase in flow rate tory pressure (supraglottic pressure) as reflected by
(Fig. 161). This alinearity in the pressure-flow relationship esophageal pressure is becoming more negative (increased
pressure difference across the upper airway).
The pharynx is not rigid and pharyngeal resistance is not
TABLE 161 constant. The nonrigid portions of the pharynx tend to
Factors Determining Upper Airway Patency become increasingly narrow with more negative inspiratory
OPEN UPPER AIRWAY CLOSED UPPER AIRWAY pressure. The collapsibility of the upper airway and tendency
for closure can be defined by the pharyngeal passive closing
PASSIVE FACTORS
pressure (PCRIT).16,17 The PCRIT values for normal people,
Larger, stiffer upper Smaller, more compliant snorers, patients with obstructive hypopneas, and patients
airway (PCRIT 0 or negative) upper airway (positive PCRIT ) with obstructive apnea are plotted in Figure 163.14 As upper
Large bony enclosure Small bony enclosure airway dysfunction increases (normal snorers apnea),
Less soft tissue (thinner More soft tissue the PCRIT is progressively more positive. During sleep, a posi-
lateral pharyngeal walls) Lower lung volume
tive pressure is needed to keep the airway open (PCRIT > 0)
Higher lung volume Supine posture
in patients with sleep apnea. In normal patients, the airway
Lateral decubitus posture
does not collapse unless a negative mask pressure is applied.
UPPER AIRWAY MUSCLE FACTORS The PCRIT is determined by applying various positive or
High upper airway muscle Low upper airway muscle negative mask pressures (Pmask) and determining the inspi-
activity activity ratory flow rate. In patients with OSA, flow decreases as
Large upper airway Low upper airway muscle mask pressure decreases from a more positive pressure (Fig.
muscle response to response to negative upper 164). The mask pressure at which flow is zero is PCRIT. The
negative pressure airway pressure inverse of the slope is the effective resistance ( pressure/
VENTILATORY CONTROL STABILITY flow) and is called the upstream resistance (Rus). The equa-
tion relating flow ( V max), mask pressure, and PCRIT
STABLE VENTILATORY DRIVE FLUCTUATING VENTILATORY
DRIVE V max = (Pmask PCRIT )/ R us
Low loop gain High loop gain Pus = Pmask in Starling resistor model
Low controller gain High controller gain
Equation 161
Low plant gain High plant gain
High arousal threshold Low arousal threshold
The relationship between flow and mask pressure can be
PCRIT = passive closing pressure of the upper airway.
modeled using a Starling resistor (Fig. 165) using Pus

P  5
Supraglottic
pressure Airflow
Greater pressure
difference across
Nose P  0 Lungs Inspiration the upper airway
0
Upper at B versus A with
airway Pressure 5 no increase in flow
A cm H2O
10
P  10
A B

P0 Pressure difference  flow  resistance

B
FIGURE 161 A higher pressure (P) difference across the upper airway (more negative supraglottic pressure) at B compared with
A does not increase airflow. This is an example of airflow limitation. The effective resistance has increased with more negative
supraglottic pressure.
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 Chapter 16 Pathophysiology of Obstructive Sleep Apnea 265

Wake Sleep (stage N1)

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

ECG

EMGgg

Airflow limitation

Flow

Phasic genioglossus activity

MTA-EMGgg

Tonic genioglossus activity

Supraglottic 0
pressure
(cm H2O)
20

FIGURE 162 With sleep onset, there is a fall in genioglossus activity and inspiratory effort and flow. This results in airflow limitation
(flat flow). Note the phasic (inspiratory) increase in genioglossus activity during stable breathing preceding sleep. ECG =
electrocardiogram; EMGgg = genioglossus electromyogram; MTA-EMGgg = rectified moving time average of EMGgg. Adapted from
Berry RB: OSAHS definitions, epidemiology, and consequences. In Carney P, Berry RB, Geyer JD (eds): Clinical Sleep Disorders, 1st ed.
Philadelphia: Lippincott Williams & Wilkins, p. 261.

(upstream pressure) = Pmask. This consists of a collapsible
segment between rigid tubes.16 As long as the intraluminal
pressure within any point of the collapsible segment is less
than PCRIT, the relationship in Figure 164 will hold. Creating
more negative pressure downstream from the collapsible
segment will not increase flow. When the intraluminal pres-
sure along the entire collapsible segment is less than the
PCRIT, no flow occurs.
During wakefulness, upper airway muscle activity main-
tains an open upper airway even if the airway is anatomically
narrow. Some upper airway muscles such as the genioglossus
(GG; tongue protruder) and palatoglossus show increased
activity with inspiration (phasic activity) (see Fig. 162),
whereas others such as the tensor velli palatini (a muscle of
the palate) show tonic (constant) activity.1820 Activation of
phasic upper airway muscles is triggered slightly before the
muscles of the respiratory pump. This allows for a stable
upper airway during inspiratory flow. The inspiratory activ-
ity of the GG muscle is affected by (1) negative intraluminal
pressure via effects on upper airway mechanoreceptors in
the laryngeal area, (2) central pattern generators in the
brainstem, and (3) influences of sleep state (wakefulness
stimulus).16 The activity of the phasic upper airway muscles
(GG) but not the tonic palatal muscles relates closely to
pharyngeal pressure. The activity of tonic upper airway
muscles appears to be more sleep statedependent (wake
> nonrapid eye movement [NREM] > rapid eye movement
[REM]).18,20
The effects of negative upper airway pressure on the GG
are mediated through a reflex neural pathway. The pathway
starts with upper airway mechanoreceptors and travels
through the superior laryngeal nerve to sensory brainstem
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266 Chapter 16 Pathophysiology of Obstructive Sleep Apnea

0
1
Slope 
PCRIT (cm H2O)

. Rus
4 Vmax

8

12

16

Condition #1 10 Condition #2

20
PCRIT
Normal Snorer Obstructive Obstructive Pmask (Pus)
hypopnea apnea
FIGURE 164 The relationship between the flow rate ( Vmax)  and various mask
* * * pressures (Pmask) in a sleeping patient. When Pmask falls below PCRIT, no flow is noted
FIGURE 163 This figure compares the values of pharyngeal passive closing pressure (Condition #1). When Pmask exceeds PCRIT (Condition #2), the flow depends on the
of the upper airway (PCRIT) for normal subjects, snorers, and patients with obstructive pressure difference (Pmask PCRIT) and the slope of the line is the inverse of the
hypopnea and obstructive apnea. The data are presented as both individual values and upstream resistance (Rus). In the Starling model, the Pmask is considered the upstream
means standard deviation (SD) for the four groups. Note the progressive increase in pressure (Pus)see Figure 165. From Gold AR, Schwartz AR: The pharyngeal critical
the mean pharyngeal PCRIT with increasing levels of pharyngeal collapsibility and airway pressure. Chest 1996;100:10771088.
obstruction (P < .01). From Gleadhill IC, Schwartz AR, Schubert N, et al: Upper airway
collapsibility in snorers and in patients with obstructive hypopnea and apnea. Am Rev
Respir Dis 1991;143:13001303.

Rigid tube Condition #2

Rus
Sealed box 10

15 9
Collapsible segment
Pin
Pus  Pcrit 10 Pds  Pcrit
Pout
A C . Pus  Pcrit
Vmax 
Rus

Condition #1 Condition #3
R

Pus  5 15 11

Pus  Pcrit Pout  10 Pus  Pcrit Pds  Pcrit

10
B D
FIGURE 165 A, Starling resistor model with pharynx assumed to be a collapsible segment with rigid tubes on the upstream
and downstream sides. The intraluminal pressure (Pin) and extraluminal pressure (Pout) are shown. B, The upstream pressure (Pus)
is less than critical closing pressure (Pcrit). No airflow occurs. Pout is the pressure surrounding the collapsible segment of the upper
airway. C and D represent the addition of +15 cm H2O pressure to the upstream side of the collapsible segment (Pus). C, The Pus is
greater than the Pcrit and airflow depends on the resistance of the upstream resistance (Rus). The collapsible segment collapses or
flutters to maintain the intraluminal pressure at its downstream end at +10 cm H2O. If flow stops, the pressure along the entire
collapsible segment suddenly becomes +15 cm H2O and flow temporarily resumes until pressure reaches +10 cm H2O and the
process repeats. The pressure downstream (Pds) from the collapsible segment is less than Pcrit. D, The Rus is lower, such that the
pressure drop across the collapsible segment is less than Pcrit (Pds > Pcrit) and flow is not limited by the collapsible segment but
depends on the resistance of the entire tube. Vmax  = flow rate. Adapted from Gold AR, Schwartz AR: The pharyngeal critical
pressure. Chest 1996;100:10771088.
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 Chapter 16 Pathophysiology of Obstructive Sleep Apnea 267

nuclei (nucleus of the solitary tract [NTS]). Neurons in the
NTS then stimulate hypoglossal motoneurons in the brain-
stem that innervate the GG via the hypoglossal nerve.
Greater upper airway inspiratory muscle activity occurs
with more negative upper airway pressure. Hypoxia and
hypercapnia could potentially modulate (increase) upper
airway muscle activity via effects on the central pattern gen-
erators or indirectly by augmenting ventilatory drive/
inspiratory effort, generating more negative upper airway
pressure (higher suction pressure). Pillar and coworkers21
administered exogeneous CO2 to normal individuals during
NREM sleep and found no significant augmentation of GG
activity. The epiglottic negative pressure was not significantly
different between baseline and CO2 inhalation. Thus, hyper-
capnia was not associated with more negative upper airway
pressure or an increase in GG activity. This study was per-
formed with subjects in the lateral sleep position. In contrast,
during monitoring in the supine position, Lo and colleagues8
did find that exogenous CO2 administration augmented GG
activity. The administration of continuous positive airway
pressure (CPAP) did not change the slope of the GG response
to hypercapnia. However, upper airway pressure was not
measured. The etiology of the effect of posture is not clear.
With sleep onset, the loss of the wakefulness stimulus on
upper airway muscles causes a decrement in their activity.
This may be mediated in part by a loss of serotonergic or
noradrenergic excitatory modulation of upper airway motor
neuron activity.5
At the onset of NREM sleep, the activity of both phasic
and tonic upper airway muscles decreases18,19,22,23 and upper
airway resistance increases24 (see Fig. 162). With stable
sleep, the activity of the GG may actually return to waking
or higher than wakefulness levels as upper airway pressure
becomes increasingly negative25 (Fig. 166). If upper airway
activity is favorable or upper airway muscle activity has
compensatory effectiveness, stable ventilation will be main-
tained. Compensatory effectiveness requires a sufficient
increase in upper airway muscle activity (stimulated by
hypercapnia and negative upper airway pressure) and that
the increase in muscle activity is effective in maintaining
upper airway patency.26
Patients with OSA tend to have higher than normal awake
basal GG activity.2729 The higher activity is believed to be
compensation for an intrinsically narrow or more collapsible

Wake Cyclical S2 Stable S2 Stable SWS

50 A B
GG mta
(%max)
0
3
GG raw
(volt)
3
25
ABD
(cm)
10
18
RC
(cm)
14
10
PEPI
(cmH2O) C
30
1 D
VT
(L) 0
1
Flow
(L/s)
1
100
SaO2
(%)
85
10s

FIGURE 166 Tracings from a patient with periods of both obstructive apnea and stable ventilation during sleep. During stable
stage N2 sleep without apneas (Stable S2), high genioglossus activity (B) is noted associated with more negative epiglottic pressure
(PEPI) (D). Note that the genioglossus activity is higher than during wakefulness. During slow wave sleep (SWS; stage N3), the
genioglossus activity is higher than stage N2 and PEPI is more negative. The inspiratory activity of the moving time average of the
genioglossus (GG mta) is higher at B than at A because epiglottic pressure (PEPI) is more negative at D than at C. ABD = abdominal
band; Cyclical S2 = stage N2 with repeated obstructive apneas; RC = chest band; SaO2 = arterial oxygen saturation; VT = tidal
volume. From Jordan AS, White DP, Lo YL, et al: Airway dilator muscle activity and lung volume during stable breathing in obstructive
sleep apnea. Sleep 2009;32:361368.
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268 Chapter 16 Pathophysiology of Obstructive Sleep Apnea
upper airway. Most patients with OSA also have a greater
than normal fall in GG activity with sleep onset.29 A reflex
activation of the GG muscle to a sudden brief pulse of nega-
tive pressure can be demonstrated.30 The response of the GG
and palatal muscles to negative pressure is reduced during
sleep.3032 During wake, patients with OSA have a greater
response in GG activity to a sudden negative pressure pulse
than normal subjects.33 The greater response to negative
pressure and higher basal GG activity allow the upper airway
to remain open during wakefulness. In contrast, the response
of the palatal muscles to negative pressure may be impaired
in OSA patients.34 Despite evidence for higher basal upper
airway muscle activity during wakefulness, the upper airways
of OSA patients are still more collapsible than those of
normal persons.35 With sleep onset, the wakeful stimulus to
GG activity is no longer present and upper airway muscle
activity falls in normal individuals and patients with OSA.
However, as noted previously, OSA patients have a greater
than normal fall in upper airway muscle activity.29 Owing to
unfavorable anatomy, the residual upper airway activity is
not sufficient to maintain an open upper airway. In Figures
166 and 167, a fall in GG activity as the patient returns
to sleep is associated with an obstructive apnea. Posture
also has important effects on airway patency,36 and some
patients with OSA have apnea or hypopnea only in the
supine position.
Arousal
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
ECG
EMGgg
Airflow
MTA-EMGgg
Esophageal
pressure
SaO2
FIGURE 167 After the arousal, genioglossus activity decreases as the patient returns to sleep and is associated with an obstructive apnea. During
the obstructive apnea, the moving time average of the genioglossus muscle (MTA-EMGgg) progressively increases and esophageal pressure swings
also progressively increase. However, the airway does not open until there is a large increase in genioglossus activity associated with an arousal.
ECG = electrocardiogram; EMGgg = electromyogram of the genioglossus muscle; SaO2 = arterial oxygen saturation.
During upper airway obstruction, phasic GG activity
increases proportionately to esophageal pressure deflections
(reflecting increased respiratory drive) (see Figs. 166 and
167).9,37,38 Stimulation of chemoreceptors by hypoxia and
hypercapnia increase inspiratory drive and esophageal pres-
sure deflections increase. At apnea termination, both GG
and palatal muscles are preferentially augmented and the
upper airway opens.9,37,38 Although it was once assumed that
increasing GG activity during obstructive apnea or hypop-
nea was driven entirely by hypoxia and hypercapnia, a study
of the effect of upper airway local anesthesia suggests that
mechanoreceptor stimulation (from increasingly negative
pressure below the site of obstruction) plays an important
role in the augmentation of GG activity.37 In Figure 168, the
top panels (Pre-lidocaine) show a progressive increase in GG
activity during apnea. After topical lidocaine anesthesia of
the upper airway, the GG activity is markedly diminished.
This implies that mechanoreceptor stimulation from increas-
ingly negative pressure below the site of obstruction results
in augmentation of GG activity.
Traditionally, a concept of a balance between negative
inspiratory pressure tending to collapse the airway and
upper airway muscle dilating forces was assumed to deter-
mine the state of the airway. However, more recently, the
concept of passive collapse at sleep onset (including return
to sleep after termination of respiratory events) has gained
Arousal
16 seconds
91%
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Airflow
Pre-lidocaine
MTA
EMG-GG
Esophageal
pressure
Post lidocaine
*
Lidocaine off for 120 min
60 cmH2O
5 sec
favor. In fact, at sleep onset, the ventilatory drive decreases
and supraglottic pressure may initially decrease (less nega-
tive) in some patients (although resistance increases). Upper
airway closure has also been documented during central
apnea in which there is no inspiration or negative collapsing
forces.39 Therefore, suction pressure during obstruction may
help keep the airway closed but is not necessary for the onset
of airway occlusion. Cyclic variations in ventilatory drive can
induce obstructive or central apneas at the nadir in drive.40
Thus, even if ventilatory drive to the respiratory pump
muscles decreases, the simultaneous reduction of neural
drive to the upper airway muscles can result in airway nar-
rowing or collapse.
LUNG VOLUME EFFECTS
Upper airway size also has a dependence on lung volume
with decreasing airway size as lung volume decreases.41,42
Chapter 16 Pathophysiology of Obstructive Sleep Apnea 269
FIGURE 168 Genioglossus activity increases with
increasing inspiratory effort during an obstructive
apnea (*). Topical lidocaine to the upper airway greatly
reduces the increase in genioglossus activity (*). After
anesthesia has worn off, genioglossus activity returns
to baseline. EMG-GG = electromyogram of the
genioglossus muscle; MTA = moving time average.
From Berry RB, McNellis M, Kouchi K, Light RW: Upper
* airway anesthesia reduces genioglossus activity during
sleep apnea. Am J Respir Crit Care Med 1997;156:
127132.
60 cmH2O
88 cmH2O
The upper airways of patients with OSA have greater lung
volume dependence than normal individuals.41 The lung
volume dependence of the upper airway may be mediated
via passive distending forces due to a downward tension
on upper airway structures during inspiration (tracheal
tug).43 Another way of thinking of the tracheal tug is a
decrease in extramural pressure surrounding the airway.
Any fall in end-expiratory volume (functional residual
capacity [FRC]) would then reduce upper airway size. FRC
is known to decrease during sleep,44 and this would tend
to predispose to airway closure. Morrell and coworkers45
demonstrated a progressive fall in end-expiratory retro-
palatal cross-sectional area as well as end-expiratory lung
volume in the breaths leading up to obstructive apnea.
Heinzer and colleagues46 found that an increase in lung
volume (induced by extrathoracic pressure) resulted
in a lower level of CPAP required to prevent airflow
limitation.
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270 Chapter 16 Pathophysiology of Obstructive Sleep Apnea
VENTILATORY CONTROL AND OSA
Ventilatory instability tends to occur when there is high ven-
tilatory drive. Hypoxia and hypercapnia from apnea coupled
with arousal at apnea termination results in a large increase
in ventilation. The increased ventilation postapnea may
reduce the arterial partial pressure of carbon dioxide
(PaCO2), and this coupled with a return to sleep reduces
ventilatory drive. The cycles of increased and decreased ven-
tilatory drive predispose to subsequent upper airway closure
and help perpetuate repetitive cycles of respiration and
apnea.2,40 As ventilatory drive fluctuates, both upper airway
muscle and diaphragmatic activity may fluctuate with apnea
or hypopnea tending to occur at the nadir of ventilatory
drive. If the patient falls asleep rapidly after arousal, the
PaCO2 may be near or below the apneic threshold, the level
of PaCO2 below which ventilation is no longer triggered
during sleep.47 If the PaCO2 falls below the apneic threshold,
a central apnea will occur. If the upper airway is closed at the
time of resumption of inspiratory effort, an obstructive
apnea will occur. This is the etiology of mixed apnea (initial
central portion, terminal obstructive portion).48 Alterna-
tively, an obstructive hypopnea or obstructive apnea may
occur as ventilatory drive and upper airway muscle activity
fall but the PaCO2 remains above the apneic threshold.49
Patients with a small difference between the sleeping
PaCO2 and the apneic threshold would be more likely to have
a central apnea on return to sleep.47,50 Of note, obstructive
apnea may occur before the nadir if inspiratory effort is
reached. If one monitors esophageal pressure in patients with
OSA, the nadir in deflections in some patients can occur two
or three breaths into the apnea (Fig. 169).
Recently, the concept of loop gain has been applied to
explain ventilatory instability. Loop gain characterizes the
response to a perturbation. For example, a patient with a
FIGURE 169 An obstructive apnea
(double-ended arrow) associated with a fall in
genioglossus activity. Note that the minimum
effort does not occur until the second
EMGgg
obstructed effort. A = timing of arousal;
EMGgg = electromyogram of the genioglossus
muscle; MTA = moving time average;
(Pes) min = minimum esophageal pressure MTA EMGgg
deflection during apnea.
Airflow
Esophageal
pressure
high loop gain may respond to a mild elevation in PaCO2
with sufficient ventilation to result in hypocapnia (over-
shoot) rather than simply bringing the system back to the
original state (eucapnia). Patients with high loop gain are
predisposed to ventilatory instability. High loop gain may be
due to high controller gain (high hypercapnic ventilatory
response) or high plant gain (large decrease in PaCO2 for a
given increase in ventilation). Plant gain is increased when
there is hypercapnia, a low dead space, and a low FRC.1,2
Loop gain = response to disturbance / the disturbance
Loop gain = controller gain (chemosensitivity)
plant gain
Controller gain = change in ventilation per change in PaCO2
(reaching chemoreceptors)
Plant gain = change in PaCO2 per change in ventilation
Equation 162
Younes and associates51 found that chemical control is
more unstable in severe compared with milder OSA patients.
Wellman and colleagues52 subsequently reported that loop
gain measured during NREM sleep was an important predic-
tor of apnea severity (respiratory disturbance index), but
only in patients with intermediate collapsibility of the pha-
ryngeal airway. Individuals with extreme airway collapsibil-
ity will have obstructive events regardless of loop gain. Thus,
it would appear that ventilatory control instability may play
an important role in the pathophysiology of airway obstruc-
tion in some patients with OSA.
STAGE R EFFECTS
The obstructive events are longest and arterial oxygen desat-
uration the most severe during REM sleep. Many patients
A
Pes min
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 Chapter 16
have obstructive events only during REM sleep or the apnea-
hypopnea index (AHI) is much higher during REM sleep.
However, the reason for the susceptibility for apnea during
REM sleep remains unclear. During REM sleep, ventilation
is irregular even in normal persons. REM sleep without
phasic eye movements is called tonic REM and with eye
movements phasic REM. There tends to be more respira-
tory irregularity during periods of bursts of eye movements
(phasic REM)53,54 (Fig. 1610). During phasic REM, there are
often periods of reduced airflow, tidal volume (VT), and
respiratory effort. The eye movement bursts are markers of
brainstem phasic REM activity that affects respiration.
Because periods of REM sleep are longest and the REM
density (number of eye movements per time) highest during
the early morning hours, it is not surprising that this is the
time of the greatest changes in ventilation during sleep in
patients with lung disease and OSA.53,55 One study in normal
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
Airflow
(nasal press)
Esophageal
pressure
FIGURE 1610 A period of reduced airflow associated with decreased inspiratory effort as reflected by esophageal pressure
deflections during REM sleep (stage R). The reduced airflow occurs during a prolonged burst of eye movements. Note that the airflow
profile is flat during inspiration, suggesting the presence of airflow limitation. EMG = electromyogram.
LGB
Diaphragm
Pathophysiology of Obstructive Sleep Apnea 271
individuals did not find a significant change in ventilation
between early and late REM sleep periods because an increase
in respiratory rate compensated for fall in VT.54 However,
patients with OSA or lung disease are more susceptible to
the phasic changes of REM sleep and VT falls with either no
change in respiratory rate or a change insufficient to main-
tain ventilation.55 During REM sleep, there is generalized
muscle hypotonia and the muscles of respiration other than
the diaphragm are less active.55 Although the diaphragm is
not affected by the generalized tonic muscle hypotonia of
REM sleep, periodic decrements in diaphragmatic activity
(inspiratory effort) do occur and are often associated with
bursts of eye movements (Fig. 1611).55 The decrements in
diaphragmatic activity are associated with reduced VT. Upper
airway muscles are also affected during REM sleep. In normal
persons during REM sleep, GG tonic activity is reduced
but phasic activity can still be detected if intramuscular
20 cm H2O
FIGURE 1611 Recording from the lateral geniculate body (LGB)
and diaphragm of a cat during rapid eye movement (REM) sleep. The
deflections in the LGB tracing are pontogeniculo-occipital (PGO)
waves that occur during bursts of eye movements. These phasic REM
changes can be associated with fractionation or decrement in the
diaphragmatic electromyogram (EMG) noted between the dashed
lines). From Orem J: Neuronal mechanisms of respiration in REM
sleep. Sleep 1980;3:251267.
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272 Chapter 16 Pathophysiology of Obstructive Sleep Apnea

EOG

EEG

0.3 L/sec

Airflow

500cc
Tidal volume

Genioglossus
EMG

Integrated
genioglossus
EMG

FIGURE 1612 Reduction in genioglossus activity during bursts of eye movements in REM sleep (stage R). EEG = electro-
encephalogram; EMG = electromyogram; EOG = electro-oculogram. From Wiegand L, Zwillich CW, Wiegand D, White DP: Changes in
upper airway muscle activation and ventilation during phasic REM sleep in normal men. J Appl Physiol 1991;71:488497.

electromyogram (EMG) electrodes are used (Fig. 1612).
During bursts of eye movements, diaphragmatic and GG
phasic activity are often decreased.56
As noted previously, many patients have obstructive
apnea only during REM sleep (REM-related OSA). However,
two studies found no greater collapsibility (PCRIT) of the
upper airway during REM than during NREM sleep.36,57 This
variance with clinical experience could be due to REM-
associated manifestations that do not affect the PCRIT mea-
surement. These might include changes in lung volume
during prolonged reductions in ventilation or impairment
of the ability of the airway to compensate for increasing
resistance. Jordan and coworkers58 studied OSA patients
who could maintain upper airway patency during some
periods of NREM sleep. Stable breathing during stage N2
was compared with cyclic REM sleep (with apneas). The
end-expiratory lung volume and peak GG EMG did not
differ. During REM sleep, the relationship between the nega-
tive epiglottic pressure (PEPI) and the phasic GG activity also
did not differ from stage N2 sleep. However, PEPI was much
less negative and the tonic GG activity was lower during
REM sleep (Fig. 1613). Perhaps lower GG tonic activity
during REM sleep makes the upper airway susceptible to
closure especially at end-exhalation when the upper airway
size is the smallest. Eckert and associates59 did not find that
patients with OSA had more REM-induced changes in upper
airway muscle activity than normal subjects. Therefore, the
normal REM-associated changes in respiratory physiology
may have greater impact on patients with susceptible upper
airway anatomy. More investigations in this area of inquiry
are needed.
GENDER AND OSA
A number of investigations have sought to determine the
pathophysiology of the higher incidence of OSA in men
than in women. Men have longer upper airways and this is
believed to predispose them to pharyngeal collapse.60 Of
note, postmenopausal women have longer upper airways
than premenopausal women.61 One study found that men
also have more fat around their upper airway than women.62
There have been no clear gender differences in loop gain,
upper airway collapsibility (PCRIT), or pharyngeal muscle
activation.6365 Pillar and associates65 found that men deve-
loped more hypopnea due to resistive loading. Because no
difference in upper airway muscle activation was noted, the
increased tendency for male upper airway narrowing was
believed to be due to anatomic factors. There have been
efforts to determine whether a difference in ventilatory
control between men and women could explain the higher
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 Chapter 16 Pathophysiology of Obstructive Sleep Apnea 273

Wake Cyclical REM Stable S2

50
GG mta
(%max) *
0
3
GG raw *
(volt)
3
25
ABD
(cm)
10
18
RC
(cm)
14
10
PEPI
(cmH2O)
30 **
1 **
VT
(L)
0
1
Flow
(L/s)
1
100
SaO2
(%)
85

FIGURE 1613 Comparing rapid eye movement (REM) sleep with obstructive apneas with breathing during stable stage N2
sleep (S2). The tonic (expiratory) genioglossus (GG) EMG is much lower (*) and the epiglottic pressure (PEPI) is much less negative (**).
ABD = abdominal band; mta = moving time average; RC = chest band; SaO2 = arterial oxygen saturation; VT = tidal volume. From
Jordan AS, White DP, Lo YL, et al: Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. Sleep
2009;32:361368.

prevalence of OSA in men. Loop gain is not different between
men and women.63 As previously noted, the apneic threshold
is the sleeping PaCO2 at which ventilation is no longer trig-
gered (see Chapter 21). Men have a smaller difference
between their sleeping PaCO2 and their apneic threshold,
predisposing them to central apnea or hyponea after periods
of hyperventilation.66,67 In summary, no clear explanation for
the gender difference in the prevalence of OSA has been
found. Anatomic differences (longer upper airway length) or
increased upper airway susceptibility to resistive loading
or falling ventilatory drive in men may be possible
explanations.
MECHANISMS OF APNEA TERMINATION
AND AROUSAL
Obstructive apnea or hypopnea termination is often associ-
ated with cortical arousals. The relationship between these
two phenomena is still the subject of investigation (Box
161). During obstructive apnea or hypopnea during NREM
sleep, upper airway muscle activity increases proportional to
inspiratory effort. Studies by Reemers and coworkers9 sug-
gested that airway opening does not occur until there is
a preferential increase in upper airway muscle activity
BOX 161
Respiratory Arousal Mechanisms
The arousal stimulus during obstructive apnea and
hypopnea appears to be proportional to the magnitude
of inspiratory effort (esophageal pressure excursions).
Hypercapnia, hypoxemia, and negative pressure stimuli
during obstructive respiratory events result in increasing
respiratory effort. However, arousal occurs when the level
of effort reaches an arousal threshold.
The arousal threshold to respiratory stimuli during NREM
sleep is increased in patients with OSA compared with
normal individuals (higher inspiratory effort is needed to
trigger arousal).
A higher arousal threshold may predispose to longer
respiratory events, but a low arousal threshold may
contribute to ventilatory instability.
Obstructive apneas and hypopneas are longer during
REM than during NREM sleep. In contrast, normal
individuals arouse from experimental mask occlusion
more rapidly in REM than in NREM sleep.
The mechanisms responsible for obstructive event
termination and respiratory arousal have similar time
courses but may be independent parallel processes. In
some studies, 2040% of obstructive event terminations
are not associated with cortical arousal.
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274 Chapter 16 Pathophysiology of Obstructive Sleep Apnea
(compared with the diaphragm) (see Figs. 166 and 167).
The preferential increase in upper airway muscle activity
was believed to be due to associated arousal. One problem
with this concept is that not all event terminations are asso-
ciated with cortical arousal (e.g., 6080% of event termina-
tions are associated with arousal). Sometimes, obstructive
event termination is associated with signs of cortical activa-
tion, although the electroencephalogram (EEG) changes
may not always meet American Academy of Sleep Medicine
(AASM) criteria.68 For example, a delta burst may be seen at
apnea termination. OMalley and coworkers69 suggested that
by using frontal electrodes, one could detect arousal in the
majority of events. Even when cortical arousal cannot be
detected, some have hypothesized a state change at the level
of the brainstem.70 These are sometimes referred to as sub-
cortical or autonomic arousals because changes in sympa-
thetic tone, heart rate, or blood pressure can occasionally be
detected in the absence of cortical changes meeting criteria
for arousal.
Younes71 has challenged the concept that arousal is an
essential component of upper airway opening. His work
found that arousal may precede, coincide with, follow, or
not occur with upper airway opening. Thus, in this view,
arousal may be associated with event termination, but what
opens the airway is a sufficient augmentation of upper
airway muscle activity by chemical and mechanical stimuli.
Thus, Younes hypothesizes that airway opening and arousal
are two separate independent phenomena that occur in par-
allel with similar time courses during obstructive respira-
tory events. Upper airway muscle activity is progressively
augmented until an upper airway opening threshold is
reached and the airway opens. Likewise, during obstructive
events, the arousal stimulus (proportional to the level of
inspiratory effort70,72,73) increases until the arousal threshold
is reached and arousal occurs. If augmentation of upper
airway muscle activity is brisk, the required degree of
muscle augmentation is not excessive, and the arousal
threshold is high, the airway could reopen without arousal
(the patient remains asleep). Evidence for this concept is
that most patients with OSA have some periods of the night
without events and, thus, are able to maintain upper airway
patency without arousal. However, this concept does not
explain event termination during REM sleep when upper
airway muscles do not necessarily augment during the event
(see Fig. 1613). In addition, whereas phasic upper airway
muscles augment with increasing inspiratory drive (and
more negative upper airway pressure), tonic upper airway
muscles do not. Tonic muscles increase their activity with a
state change (arousal). Thus, arousal may play a role in ter-
mination of some obstructive events. Even if arousal is not
essential to upper airway opening, repeated arousals are
thought to contribute to daytime sleepiness (along with the
associated hypoxemia).74,75
The mechanisms that contribute to respiratory arousal are
also of interest and still incompletely understood. Whereas
hypercapnia and hypoxia drive the increase in respiratory
effort, the level of effort rather than individual values of
hypoxia or hypercapnia seems to trigger arousal.70,72,73 Thus,
the level of effort is an index of the combined arousal stimu-
lus. Studies have suggested that information from upper
airway mechanoreceptors may contribute to the arousal
stimulus.76,77 In NREM sleep, arousal appears to occur when
inspiratory effort reaches an arousal threshold. Normal
subjects tend to arouse during mask occlusion when suction
pressure reaches 20 to 40 cm H2O. In contrast, many
patients with OSA arouse only after esophageal pressure
reaches 60 to 80 cm H2O.70,73,78 The increased arousal
threshold in OSA patients is probably due in part to chronic
sleep deprivation or hypoxemia. Withdrawal of CPAP for
even three nights has been shown to increase the arousal
threshold in OSA.78 However, chronic CPAP treatment does
not restore the arousal threshold to normal. Patients with
OSA could have an intrinsically increased respiratory arousal
threshold. Another possible explanation for an elevated
arousal threshold is damage to mechanoreceptors from years
of snoring or to chemoreceptors from repetitive nightly
stimulation. Support for this idea comes from studies
showing that upper airway sensation is impaired in patients
with OSA.79 A study of respiratory-related evoked potentials
(RREPs) in patients with mild OSA suggested that there is a
sleep-specific blunted cortical response to inspiratory occlu-
sion.80 At least in these milder patients, there was no evi-
dence of impaired mechanoreceptor function because the
RREP was normal during wakefulness. One study found that
the prolongation in event duration that occurs overnight in
patients with OSA is secondary to a blunting of the cortical
response as the level of inspiratory effort at apnea termina-
tion increased during the night.81 Another study found that
the within-night variation in the arousal threshold followed
the cycles of NREM sleep82 with a higher arousal threshold
associated with higher EEG delta power (deeper sleep).
Sforza and colleagues83 studied the within-night changes in
the arousal threshold associated with respiratory events and
found that the arousal threshold tended to peak during the
first 3 hours of sleep, plateau, and then decrease slightly in
the last hour of sleep. They did find a mild increase in apnea
duration over the night. The authors concluded that their
findings showed the arousal threshold was not dependent on
sleep fragmentation (which should have continued to worsen
during the entire night) and might reflect circadian or
homeostatic rhythms. Another explanation is that greater
delta power (sleep depth) occurs in the early part of the
night82 and greater sleep depth delayed arousal.
It is worth noting that the apnea duration (time to arousal)
depends on both the arousal threshold and the rate of
increase in inspiratory effort (respiratory response to
arousal).70 For example, the addition of supplemental oxygen
results in longer apneas (reduction in rate of augmentation
in inspiratory effort) but event termination occurs at similar
levels of esophageal pressure (similar arousal threshold).70 If
one believes that airway opening is independent of arousal,
a similar scheme can still be invoked with the determinants
of event duration being the rate of upper airway muscle
augmentation and the airway opening threshold.
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In REM sleep, the arousal mechanisms are less well
understood. Esophageal pressure deflections do not show a
steady increase (see Fig. 1613). However, normal subjects
arouse more quickly from mask occlusion during REM sleep
than during NREM sleep.70,84 In contrast, patients with OSA
have the longest apneas and most severe desaturation during
REM sleep.85
The reasons for the delayed arousal (longer event dura-
tion) during REM sleep in OSA patients are not known. The
slower and erratic augmentation of respiratory drive that
occurs during REM sleep could delay arousal and event ter-
mination even if the arousal threshold is similar to that of
NREM sleep.86 Conversely, there could be an increase in the
arousal threshold during REM compared with NREM sleep
in some OSA patients with chronic REM sleep fragmenta-
tion. Certainly, some OSA patients exhibit a tremendous
increase in eye movements during REM sleep on the first
night on CPAP. This may be evidence of prior REM sleep
fragmentation or deprivation. Prior sleep disturbance could
increase the arousal threshold. Zavodny and coworkers87
found evidence that sleep fragmentation from acoustic
stimuli impaired the arousability to resistive loading in stage
BOX 162
Factors Associated with More Severe Arterial
Oxygen Desaturation
Higher BMI
More effect during REM than NREM sleep.
More effect supine > lateral sleep.
More effect men > women.
Lower baseline awake supine PaO2 or SaO2
Lower ERV (FRC RV).
Low FRCobesity.
High RVobstructive airways disease (COPD).
Longer event duration.
Greater change in V T (hypopnea).
Short ventilatory period between apnea.
REM sleep versus NREM sleep (REM events are also
longer).
Supine versus lateral position.
BMI = body mass index; COPD = chronic obstructive pulmonary disease;
ERV = expiratory reserve volume; FRC = functional residual capacity;
NREM = nonrapid eye movement; PaO2 = arterial partial pressure of
oxygen; REM = rapid eye movement; RV = residual volume; SaO2 = arterial
oxygen saturation; V T = tidal volume.

N2 sleep but not in REM sleep. An effect of sleep fragmenta-

tion was seen during early REM sleep. However, because
most REM sleep occurred in the second part of the night,
10 mmHg decrease in PaO2
sleep fragmentation did not impair arousal when REM sleep
causes a greater desaturation
for the entire night was analyzed. Thus, to date, there is no starting on the steeper part of
compelling evidence that sleep fragmentation increases the curve
either respiratory event duration or the respiratory arousal 100
threshold during REM sleep.
% Oxygen saturation (SaO2)

80
UPPER AIRWAY SENSATION
60
There is evidence that upper airway sensation is impaired in
patients with OSA.79 This could be due to years of trauma
from snoring. It is unclear whether damage to upper airway 40
mechanoreceptors could be playing a role in the pathogen-
esis of OSA in some patients. 20

ARTERIAL OXYGEN DESATURATION 0

Patients with a similar AHI may have vastly different degrees
of arterial oxygen desaturation. Box 162 lists factors deter-
mining the severity of arterial oxygen desaturation. Studies
of breath-holding in normal subjects suggest that the rate of
fall in the SaO2 is inversely proportional to the baseline SaO2
and to the lung volume (oxygen stores) at the start of breath-
hold.88 The rate of fall is disproportionately higher at low
lung volumes secondary to increases in ventilation-perfusion
mismatch. A study of OSA patients by Bradley and associ-
ates89 found that the severity of nocturnal arterial oxygen
desaturation was related to several factors, including the
awake supine arterial partial pressure of oxygen (PaO2), the
percentage of sleep time spent in apnea, and the expiratory
reserve volume (ERV). Patients with a baseline PaO2 of 55
to 60 mm Hg are on the steep part of the oxyhemoglobin
saturation curve (Fig. 1614). A small fall in PaO2 results
20 40 60 80 100
PaO2 (mmHg)
Oxygen-hemoglobin Saturation Curve
FIGURE 1614 The same drop in the arterial partial pressure of oxygen (PaO2) causes
a bigger drop in the SaO2 on the steeper part of the oxygen-hemoglobin saturation
curve.
in significant desaturation. Whereas apnea duration is an
obvious factor in the severity of desaturation, the length of
the ventilatory period between events is also important.
Some patients do not completely resaturate between events
because they quickly return to sleep and the airway closes
again. Long event duration and short periods between apneas
mean the percentage of total sleep time spent in apnea is
high. A small ERV is associated more with severe arterial
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276 Chapter 16 Pathophysiology of Obstructive Sleep Apnea
FIGURE 1615 A total night view shows the hypnogram with rapid eye movement (REM) sleep shown by horizontal bars. The patient had almost no events except
during REM sleep, but during REM sleep, the desaturation was significant. SaO2 = arterial oxygen saturation.
oxygen desaturation during respiratory events. The ERV is
the difference between the functional residual capacity (FRC;
end-expiratory volume) and the residual volume (RV). A
small ERV is usually due to a low FRC, a high RV, or both.
In obesity, the FRC is reduced. A lower FRC is associated
with lower oxygen stores before a respiratory event. Tidal
breathing at low lung volumes results in substantial small
airway closure (below the closing volume). This increases the
amount of ventilation-perfusion mismatch (no ventilation
reaches some alveoli). A high RV is usually due to airtrap-
ping associated with obstructive airways disease. The pres-
ence of obstructive airway disease also causes more
ventilation-perfusion mismatch (see Chapter 10). Low
oxygen stores at the start of apnea and ventilation-perfusion
mismatch both contribute to a more rapid and more severe
drop in the SaO2 during apnea or reduced ventilation
(hypopnea).
Clinically, the groups of OSA patients with severe desatu-
ration include patients with a low PaO2 for any reason (severe
obesity, daytime hypoventilation, and chronic obstructive
pulmonary disease [COPD]). In fact, some patients can have
significant desaturation after events as short as 10 to 15
seconds. The severity of desaturation also depends on sleep
stage. As noted previously, in most OSA patients, the longest
apneas and most severe desaturations occur in REM sleep
(Fig. 1615).85 Some studies also have suggested that at
equivalent apnea length, the severity of desaturation is
worsened in obstructive compared with central apnea.90 A
recent large study of the Wisconsin cohort found that a
higher BMI was associated with oxygen desaturation severity
independent of age, gender, sleeping position, baseline SaO2,
and event duration.91 A higher body mass index (BMI) had
a greater effect on desaturation in REM than in NREM sleep.
In addition, a fall in VT had a greater effect on arterial oxygen
desaturation when the BMI was higher. The predicted change
in the SaO2 was also higher in the supine position than in
the lateral position, in men than in women, and in smokers
than in nonsmokers. Another study found that obstructive
events in the supine position tended to be longer, were asso-
ciated with more severe desaturation, and were more likely
to be associated with an arousal at event termination.92
As previously mentioned, REM sleep is associated with
more severe desaturation than NREM sleep.85,93 Oksenberg
and coworkers also found that supine REM sleep is associ-
ated with more severe arterial oxygen desaturation than non-
supine REM sleep. This was not due to longer event
duration.93 Thus, one would expect the most severe arterial
oxygen desaturation to usually occur during supine REM
sleep.
CLINICAL REVIEW QUESTIONS
1. Which of the following factors may help explain the
greater prevalence of OSA in men than in women?
A. Longer upper airway length in men.
B. Higher PCRIT (more positive) in men.
C. Less pharyngeal muscle activation.
D. Higher loop gain in men than in women.
2. Breathing through the nose rather than the mouth causes
more negative supraglottic airway pressure during inspi-
ration (e.g., 6 cm H2O with nasal breathing, 2 cm H2O
with oral breathing). Which route of breathing is associ-
ated with greater phasic activity of the GG muscle?
A. Oral breathing route.
B. Nasal breathing route.
3. Which of the following would NOT predispose to upper
airway narrowing or closure?
A. Falling ventilatory drive.
B. Higher FRC.
C. Less negative upper airway pressure.
D. Higher PCRIT.
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 Chapter 16
4. Higher BMI is associated with worse arterial oxygen
desaturation in OSA patients.
Which of the following is true about the effect of BMI on
desaturation?
A. REM > NREM.
B. Lateral position > supine.
C. Women > men.
5. Which of the following is NOT true about REM com-
pared with NREM sleep?
A. Higher PCRIT.
B. Longer apneas.
C. Lower tonic upper airway muscle activity.
D. More severe arterial oxygen desaturation.
6. The arousal stimulus (and arousal threshold) is best
related to which of the following?
A. Hypoxemia.
B. Hypercapnic.
C. Hypoxia and hypercapnia.
D. Level of inspiratory effort.
Answers
1. A. Longer upper airway length in men. No clear differ-
ence in the PCRIT, upper airway muscle activation, or loop
gain have been demonstrated in men compared with
women.
2. B. Negative upper airway pressure augments phasic
upper airway muscle activity.
3. B. Upper airway size decreases with falling lung volume.
A higher FRC would not predispose to airway closure or
narrowing.
4. A. BMI has more effect on desaturation in men com-
pared with women and supine compared with lateral
sleep.
5. A. Studies have not found a higher PCRIT during REM
sleep.
6. D.
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Berry RB: Dreaming about an open upper airway. Sleep 2006;
29:429430.
Zavodny J, Roth C, Bassetti CL, et al: Effects of sleep fragmenta-
tion on the arousability to resistive loading in NREM and REM
sleep in normal men. Sleep 2006;29:525532.
Findley LJ, Ries AL, Tisi GM, Wagner PD: Hypoxemia during
apnea in normal subjects: mechanisms and impact of lung
volume. J Appl Physiol 1983;55:17771783.
Bradley TD, Martinez D, Rutherford R, et al: Physiological
determinants of nocturnal arterial oxygenation in patients with
obstructive sleep apnea. J Appl Physiol 1985;59:13641368.
Series F, Cormier Y, La Forge J: Influence of apnea type and
sleep stage on nocturnal postapneic desaturation. Am Rev
Respir Dis 1990;141:15221526.
Peppard PE, Ward NR, Morrell MJ: The impact of obesity on
oxygen desaturation during sleep disordered breathing. Am J
Respir Crit Care Med 2009;180:788793.
Oksenberg A, Khamaysi I, Silverberg DS, Tarasiuk A: Associa-
tion of body position with severity of apneic events in patients
with severe nonpositional obstructive sleep apnea. Chest
2000;118:10181024.
Oksenberg A, Arons E, Nasser K, et al: REM-related obstruc-
tive sleep apnea: the effect of body position. J Clin Sleep Med
2010;6:343348.
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Consequences of Obstructive
Sleep Apnea and the Benefits
of Treatment
Chapter Points
The nocturnal consequences of OSA vary with severity.
Possible changes include episodic hypercapnia,
hypoxia, negative intrathoracic pressure, increases in
pulmonary and systemic pressure, cyclic slowing then
speeding of heart rate, and surges of sympathetic tone
at event termination. Most studies show that the
cardiovascular consequences are most closely related
to the severity of hypoxemia.
Patients with untreated OSA often have elevated
post-awakening AM blood pressure, high daytime
sympathetic tone, and decreased heart rate variability.
The best evidence of increased mortality in untreated
OSA is for men, with moderate to severe OSA, with an
approximate age range of 60 years (4070 in other
studies).
Observational studies suggest that OSA patients
effectively treated with CPAP have normal survival, all
other factors being equal.
The severity of daytime sleepiness increases with
higher AHI but there is substantial variability. Other
PSG indices such as the arousal index do not have
significantly higher correlations with subjective or
objective sleepiness than the AHI.
OSA patients are at increased risk for motor vehicle
accidents (especially if there is a history of sleepiness
at the wheel). Effective CPAP treatment can reduce the
risk of motor vehicle accidents.
Patients with OSA may fail to have a fall in blood
pressure with sleep (nondippers). Clinical cohorts with
hypertension or resistant hypertension have a high
prevalence of OSA. Although investigations differ,
effective CPAP treatment likely is associated with a
small decrease in 24-hour blood pressure.
OSA in the absence of lung disease or diastolic
dysfunction is associated with daytime pulmonary
hypertension in 20% to 40% of patients. The
Chapter 17
pulmonary hypertension is usually of a mild nature
(unless other factors are present).
Untreated OSA is associated with nocturnal
arrhythmia, although the incidence is low. In some
cases, effective treatment will improve arrhythmias.
Untreated OSA is associated with an increased
incidence of recurrence of Afib after cardioversion.
Observational studies suggest that untreated OSA is
associated with a higher risk of adverse outcomes in
patients with CAD.
Untreated OSA is associated with a higher incidence of
stroke. In stroke patients, CPAP treatment of OSA can
reduce mortality.
Untreated OSA can worsen nocturia and CPAP
treatment can improve this manifestation.
Pediatric OSA has significant neurobehavioral
consequences that can be improved with treatment.
This chapter reviews the consequences of untreated obstruc-
tive sleep apnea (OSA) and the benefits of treatment. Many
of the studies discussed are cross-sectional population-based
investigations looking for associations between the preva-
lence of a cardiovascular consequence (e.g., hypertension) at
a given time with the severity/presence of OSA (various
levels of apnea-hypopnea index [AHI]). Prevalence is the
amount of disease in a given population. Others follow a
population over a period of time and determine the amount
of new cases (incidence of a given disease). These studies
determine the risk of developing consequences at various
levels of AHI. The results of population-based studies may
also vary depending on the group to be evaluated. It is always
worth noting that investigations of clinic-based versus
asymptomatic individuals randomly selected may well be
different.
Considering the effects of continuous positive airway
pressure (CPAP) treatment on consequences of untreated
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282 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
OSA, it is important to understand that observational studies
are less convincing than randomized controlled trials. There
is always the concern that patients who adhered to CPAP
treatment are somehow more compliant with other medical
therapy as well and, therefore, more likely to have better
outcomes. A study by Platt and colleagues1 found CPAP
users were more adherent in taking lipid-lowering medica-
tions. However, another study by Villar and coworkers2
found that patients adherent or nonadherent to CPAP did
not differ in their adherence to medication. Both of these
studies relied on prescriptions filled or patient report, so
actual medication use could differ. There are a number of
ethical and experimental considerations to designing a study
to prove a benefit of CPAP treatment on cardiovascular out-
comes. With the widespread knowledge of CPAP, it is diffi-
cult to design a study with effective blinding and a satisfactory
control treatment (e.g., subtherapeutic CPAP).3
PATHOPHYSIOLOGY
During normal nonrapid eye movement (NREM) sleep,
there is a decrease in metabolic rate, sympathetic nerve
activity, blood pressure, and heart rate, whereas vagal tone
increases compared with wakefulness.4,5 OSA changes this
normal pattern considerably46 (Fig. 171). Cycles of hypoxia
and CO2 retention elicit changes in sympathetic and para-
sympathetic activity. Hypoxia and hypercapnia increase ven-
tilatory drive and obstructed inspiratory efforts create
negative intrathoracic pressure (sometimes reaching 80 cm
H2O). The negative pressure increases venous return to the
right side of the heart (increased right ventricular [RV]
preload) and the hypoxia causes pulmonary vasoconstric-
tion (increased RV afterload). The right ventricle may dilate
and the septum bulge into the left ventricle, impairing left
ventricular (LV) filling and decreasing stroke volume. Nega-
tive intrathoracic pressure increases the transmural pressure
FIGURE 171 Pathophysiology of the
effects of obstructive sleep apnea (OSA) on
the cardiovascular system. BP = blood
pressure; HR = heart rate; LV = left
ventricular; PCO2 = arterial partial pressure of
carbon dioxide; PNA = parasympathetic PNA Arousal
nervous system; PO2 = arterial partial
pressure of oxygen; SNA = sympathetic
nervous activity. From Bradley TD, Floras JS:
Obstructive sleep apnea and its cardiovascular SNA
Catechols
consequences. Lancet 2009;373:8293.
HR BP
across the left ventricle walls and increases the effective after-
load. The cycles of increased sympathetic tone6 (Fig. 172)
increase systemic vascular resistance. Arousal at apnea ter-
mination is associated with a large increase in sympathetic
tone and decreased vagal tone with the result that blood
pressure and heart rate increase. High sympathetic tone is
still present during wakefulness (see Fig. 172) and associ-
ated with impaired vagally mediated heart rate variability.
Intermittent hypoxia causes oxygen free radical production
and activates inflammatory pathways that can predispose to
atherosclerosis and thrombosis.
MORTALITY
In patients with OSA, frequent coexisting conditions such as
hypertension and obesity make analysis of the impact of
OSA on survival difficult. It is unlikely that a randomized
long-term trial of treatment of OSA versus observation is
now possible for ethical reasons. Most of the information we
have about mortality and OSA is from retrospective studies
or prospective observational studies. Some of the studies are
from clinical cohorts that would be expected to have a
higher prevalence of disease, but such studies are subject to
referral bias. Other studies are from large population-based
cohorts that are free of referral bias but have a relatively low
number of patients with severe OSA. Some studies have ana-
lyzed all-cause mortality and others looked at cardiovascular
mortality.
An early retrospective study by He and associates7 showed
a decreased survival in untreated patients with an apnea
index (AI) greater than 20/hr. Patients with an AI greater
than 20/hr who were treated with tracheostomy or CPAP did
not have a decreased survival. The causes of death in the
patients were not documented. Lavie and coworkers8
reviewed the results on 1620 patients diagnosed with OSA
between 1976 and 1988. Fifty-seven patients had died by
Obstructive sleep apnea
PO2 PCO2 Intrathoracic pressure
Myocardial Oxidative stress
O2 delivery Inflammation
Endothelial dysfunction
Hypertension
Atherosclerosis
Myocardial ischemia LV wall tension
LV hypertrophy and failure Cardiac O2 demand
Cardiac arrhythmias
Cerebrovascular disease
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 Chapter 17
AWAKE
Normal OSA
A B
FIGURE 172 A, Recordings of sympathetic nerve activity (SNA) during wakefulness in patients with obstructive sleep apnea (OSA) and matched controls show high levels of
SNA in awake patients with sleep apnea. B, Recording of arterial blood pressure (BP) and SNA in the same subject awake, during rapid eye movement (REM) sleep with obstructive
apnea (OSA-REM), and during REM sleep on continuous positive airway pressure (CPAP-REM). A and B, From Somers VK, Dyken ME, Clary MP, Abboud FM: Sympathetic neural
mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:18971904.
1990 with 53% of the deaths due to respiratory and cardio-
vascular causes. Excess mortality was noted in men of 30 to
50 years of age with OSA but not in patients older than 70
years of age. Lavie and colleagues9 later published results of
a sleep clinic cohort (19912000) consisting of 14,589
patients and found that the hazard of mortality was higher
in male patients with moderate and severe OSA compared
with the general population. The results were significant for
patients younger than 50 years of age. Another analysis of a
similar cohort sought to determine the factors associated
with mortality in OSA patients.10 The study found that the
risk of mortality in patients with OSA was increased by the
presence of co-morbidities. For patients younger than 62
years, increased mortality was associated with the presence
of heart failure or diabetes mellitus. For OSA patients older
than 62 years, predicators of increased mortality included
chronic obstructive pulmonary disease, congestive heart
failure, and diabetes mellitus.10 Older patients (age > 65
years) with mild to moderate OSA appear to be resistant to
the adverse effects of OSA on mortality.11
Marshall and associates12 found an increase in all-cause
mortality associated with moderate to severe OSA in a
population-based study. Marin and coworkers13 studied a
clinic population of men and found an increase of fatal and
nonfatal cardiovascular events for severe OSA compared
with normal individuals, snorers, patients with mild OSA,
and patients with OSA on CPAP treatment (Fig. 173). Yaggi
and colleagues14 published data on another cohort referred
to a sleep clinic and found an increased mortality in severe
Consequences of Obstructive Sleep Apnea and the Benefits of Treatment 283
AWAKE CPAP-REM
SNA
RESP
150 150
100 100
BP 50 50
0 0
OSA-REM
SNA
RESP OSA OSA
250
200
150
BP 100
50
0
10 sec 10 sec
OSA patients. Young and associates15 published results from
the Wisconsin Sleep Cohort and found that severe OSA
patients had an increased risk of all-cause mortality. The
results of this study were adjusted for gender. Punjabi and
coworkers16 published results on a large population cohort
from the Sleep Heart Health Study. There was an increase in
mortality for the severe OSA patients who were male and
aged 40 to 70 years. In this study, statistical corrections for
the effects of age, BMI, and gender (when appropriate) were
performed.
Summarizing the results, there is strong evidence for an
increased mortality in untreated middle-aged male patients
with severe OSA (Table 171). Indeed, two clinic-based
population studies included only or predominantly men.
Conversely, the Wisconsin Cohort data did not show a sex
difference in the increased mortality associated with severe
OSA. However, relatively few patients had severe OSA in this
study. It seems likely that women with untreated severe OSA
also have increased mortality, but the evidence for this
increased mortality is not as strong as that for men. There is
also the controversy about whether patients who are not
sleepy have an increased risk of cardiovascular morbidity.
Evidence from the Sleep Heart Health Study16 found that
adverse outcomes correlated more with measures of oxygen-
ation than with sleepiness (or impaired sleep), suggesting
that intermittent hypoxemia rather than indices of sleep
fragmentation is associated with increased mortality. Con-
versely, the Wisconsin-based cohort15 found an increase in
cardiovascular mortality with severe OSA that was present
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284 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment

35 OSA No OSA General population

Controls
30 Snorers P < 0.001 P < 0.001
Cumulative incidence of

Mild OSAH
fatal CVS events (%)

25 Severe OSAH 50 P = 0.01 P = 0.04 P = 0.02

OSAH with CPAP
20 46

Proportion of total sudden deaths

Severe
40 41
15

from cardiac causes (%)

OSA

10
30
30 29
5
26 25
24
0 20 21
0 36 72 108 144 20
A 16
10 12
9
35
Controls
Snorers
0
30
non-fatal CVS events (%)

Midnight 6 a.m. Noon 6 p.m.

Cumulative incidence of

Mild OSAH Severe
25 Severe OSAH OSA
OSAH with CPAP
20
15
10
5 in the morning. From Gami AS, Howard DE, Olson EJ, Somers VK: Day-night pattern of
0
0 36 72 108 144
B Months
FIGURE 173 Cumulative incidence of fatal (A) and nonfatal (B) cardiovascular events
(CVS) in controls, snorers, and patients with mild or severe obstructive sleep apnea
(OSA). The patients with OSA treatment with continuous positive airway pressure (CPAP)
are also shown. Patients with severe OSA had increased cumulative adverse events.
OSAH = obstructive sleep apnea-hypopnea. A and B, From Marin JM, Carrizo S, Vicente
E, Agusti AGN: Long term cardiovascular outcomes in men with obstructive sleep apnea-
hypopnea with or without treatment with continuous positive airway pressure: an
observational study. Lancet 2005;365:10461053.
irrespective of symptoms of sleepiness. The controversy con-
tinues, but it seems likely that the severity of oxygen desatu-
ration due to OSA is the major factor associated with
increased cardiovascular morbidity.
The time of sudden death appears to be different for
patients with OSA. Gami and colleagues17 found that for
patients with OSA, the relative risk of sudden death from
cardiac causes from midnight to 6 AM was 2.57 (95% confi-
dence interval 1.873.52) compared with other times during
the day. People with OSA have a peak in sudden death from
cardiac causes during the sleeping hours, which contrasts
strikingly with the nadir of sudden death from cardiac causes
during this period in people without OSA and in the general
population. In patients without sleep apnea, the risk of
sudden death was greatest in the morning hours after awak-
ening (Fig. 174).17
EXCESSIVE DAYTIME SLEEPINESS AND
NEUROCOGNITIVE DYSFUNCTION
Excessive daytime sleepiness is a cardinal manifestation of
OSA. However, the severity of this symptom is extremely
5:59 a.m. 11:59 a.m. 5:59 p.m. 11:59 p.m.
Time of day
FIGURE 174 Day-night pattern of sudden death from cardiac causes in 78 persons
with and 34 persons without obstructive sleep apnea (OSA) and in the general
population. For OSA patients, the most common time of sudden death is during the sleep
period. In normal individuals without OSA, the most common time of sudden death is
sudden death in obstructive sleep apnea. N Engl J Med 2005;352:12061214.
variable. Chronic sleep deprivation and/or fragmentation
from respiratory events is believed to be the major cause of
sleepiness, although hypoxemia may also play a role. Normal
individuals subjected to experimental sleep fragmentation
without hypoxemia develop subjective and objective daytime
sleepiness.18,19 Attempts at finding abnormalities demon-
strated on polysomnography that correlate highly with sub-
jective or objective sleepiness have not been very successful.
Johns20 found the Epworth Sleepiness Scale (subjective sleep-
iness) to correlate with the respiratory distress index (RDI)
in a group of 165 patients with OSA (r = 0.439) and slightly
less with the minimum arterial oxygen saturation (SaO2; r =
0.404). Guilleminault and associates21 found no polysom-
nographic variable to be significantly correlated with sleepi-
ness as assessed by the multiple sleep latency test (MSLT).
Roehrs and coworkers19 analyzed data from 466 patients
using multiple regression analysis and found daytime sleepi-
ness as assessed by the MSLT had a slightly higher correlation
with the respiratory arousal index (r = 0.36) than indices of
hypoxemia (r = 0.34). Cheshire and colleagues found the
arousal index to correlate with impaired cognitive function
testing but not objective daytime sleepiness.22 Bennett and
associates23 found that the AHI, cortical arousal index
(central and frontal electroencephalogram [EEG]), sleep dis-
turbance based on a neural network model, and a body
movement index correlated with objective daytime sleepi-
ness. The correlation between excessive sleepiness and the
indices of sleep disturbance was only slightly higher than the
correlation between sleepiness and the AHI. The body move-
ment index (based on video recording rather than EEG) and
the neural network had the highest correlation coefficients.
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 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment 285

TABLE 171
Increased Mortality and Obstructive Sleep Apnea
AUTHOR SELECTION PARTICIPANTS FINDINGS
Punjabi, 200916 Sleep Heart Health 6441 patients Severe OSA AHI > 30/hr associated with
Population-based Cohort Average f/u 8.2 yr increased mortality only in men
Severe OSA N = 341 4070 yr old.
Measures of sleep-related hypoxemia
but not sleep fragmentation were
associated with increased mortality.
Marin, 200513 Snorers, OSA, and MEN ONLY Men with severe OSA AHI > 30/hr had
Clinical cohort matched control 264 healthy men increased incidence of fatal (MI, CVA)
sleep clinic population 337 simple snorers and nonfatal adverse cardiovascular
recruited 403 untreated mild to events (MI, CVA, CABPG, coronary
moderate OSA angiography) compared with control
235 severe OSA untreated group, mild OSA group, and CPAP
372 OSA treated with CPAP group.
Odds ratio fatal CVE 2.87
Odds ratio nonfatal CVE 3.17
Severe group treated with CPAP did not
have increased risk compared with
normal men.
Yaggi, 200514 Patients referred to sleep 1022 patients (77% male) OSA (AHI > 5/hr) was associated with
Clinical cohort clinic 697 had OSA increased risk of death from any
PSG for diagnosis cause.
Adjustments for age, sex,
race, smoking status,
BMI, DM, Afib, HTN
Lavie, 20059 Patients referred to sleep N = 14,589 RDI > 30/hr males had higher mortality
Clinical cohort clinic 372 deaths after median but only in males aged < 50 yr.
f/u of 4.6 yr
Young, 200815 18-yr mortality f/u N = 1522 All-cause mortality higher in severe OSA
Population-based PSG at baseline Severe OSA N = 63 (AHI > 30/hr) vs. no OSA even when
Adjustments for age, CPAP-treated patients eliminated.
gender, BMI, DM, The results were not changed based on
cholesterol, mean BP the presence or absence of sleepiness.
Marshall, 200812 Prospective observational 397 participants moderate Moderate to severe OSA (AHI > 15/hr)
(Busselton Health Home sleep testing to severe OSA N = 18 had greater risk of all-cause mortality
Study) 14-yr f/u 380 free from MI and CVA compared with no OSA.
Population-based Adjustments for age, at baseline Mild OSA had no increased risk.
gender, BMI, DM, 18 AHI > 15/hr
cholesterol, mean BP 77 AHI 5 to <15/hr
285 no OSA
Afib = atrial fibrillation; AHI = apnea-hypopnea index; BMI = body mass index; BP = blood pressure; CABPG = coronary artery bypass grafting; CPAP = continuous
positive airway pressure; CVA = cerebrovascular accident; CVE = complex ventricular event; DM = diabetes mellitus; f/u = follow-up; HTN = hypertension; OSA =
obstructive sleep apnea; PSG = polysomnography; RDI = respiratory distress index.

Routine EEG analysis based on sleep staging or EEG
arousals may not be sensitive enough to detect all the adverse
effects of respiratory disturbance. For example, noncortical
arousals from respiratory events or other causes may result
in daytime sleepiness.24 It may also be possible that long
periods of airflow limitation with high respiratory effort
without discrete arousal could be associated with symptoms.
This pattern commonly occurs in children with OSA who
develop behavioral changes and impaired school perfor-
mance without frequent discrete arousals.25,26 Findings from
the Sleep Heart Health Study show an increase in sleepiness
with higher AHI, but the relationship is weak.27 There is also
evidence from several studies that hypoxemia may be a
factor associated with impaired cognition in patients with
OSA.28 For many patients, a number of factors other than
OSA contribute to daytime sleepiness including insufficient
sleep and medication side effects. There is also considerable
individual variability in the ability to tolerate sleep fragmen-
tation. Therefore, it should not be surprising that there is
only a modest correlation between the AHI and subjective
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286 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
or objective measures. Of note, studies of heart failure
patients with OSA often show a large proportion do not
complain of daytime sleepiness.29 It should also be noted that
effective treatment of sleepy OSA patients (e.g., CPAP) does
not always abolish daytime sleepiness.
AUTOMOBILE ACCIDENTS AND SLEEP APNEA
The true increase in risk of patients with OSA having an
automobile accident is difficult to determine. However, pub-
lished studies have found a two to three times greater risk in
untreated patients with OSA.3032 Clearly, not all patients
with sleep apnea are at high risk of having an auto accident.
It appears that the presence of sleep apnea plus a history of
a previous accident (or frequent falling asleep at the wheel)
identifies a group of patients with especially high risk. The
decision of whether to report a patient with OSA to a motor
vehicle licensing agency is a difficult one. A balance between
patient confidentiality and protection of the public is
required. A committee of the American Thoracic Society has
issued the following recommendations33: In those jurisdic-
tions in which conditions such as excessive daytime sleepi-
ness caused by sleep apnea may be construed as reportable
events, we recommend reporting to licensing bureaus if: (a)
the patient has excessive daytime sleepiness, sleep apnea, and
a history of a motor vehicle accident or equivalent level of
clinical concern; and (b) one of the following circumstances
exists: (i) the patients condition is untreatable or is not ame-
nable to expeditious treatment (within 2 months of diagno-
sis) or (ii) the patient is not willing to accept treatment or is
unwilling to restrict driving until effective treatment has
been instituted. The committee also noted that it is the phy-
sicians responsibility to notify every patient with sleep apnea
that driving when sleepy is unsafe. Some form of written
documentation that the patient understands this warning is
prudent. A statement concerning sleep apnea and commer-
cial motor vehicle operators by a joint task force of the Amer-
ican College of Chest Physicians, the American College of
Occupational and Environmental Medicine, and the National
Sleep Foundation34 provides guidance concerning the evalu-
ation, treatment, and return to work of drivers with sus-
pected or known OSA.
It is concerning that large financial tort settlements have
been brought successfully against some physicians for failure
to report a person with a medical condition who was subse-
quently involved in a serious traffic accident. Each state has
its own laws, and local medical societies have guidelines.
However, in the end, the decision rests with the judgment of
the treating physician. In some states, reporting is done to a
health agency rather than directly to the motor vehicle
licensing agency. Note that reporting does not always result
in the loss of the patients license.
To date, there is no objective test that can quantify a
patients degree of driving impairment. The use of the main-
tenance of wakefulness test (MWT) and MSLT were dis-
cussed in Chapter 14. The MWT is the appropriate test to
assess the ability to stay awake. However, MWT results may
not generalize to the real world in which sleep deprivation
and other factors are operative. There have been promising
attempts at developing protocols using driving simulators,35,36
but results in a simulator may not correlate with driving
performance. A study of untreated OSA patients36 found an
MWT mean sleep latency (MSL) less than 19 minutes was
associated with impairment on a driving simulator. The same
group extended this work by testing patients with OSA
during actual 90-minute driving sessions on the road with a
driving instructor intervening if necessary (the test car had
two steering wheels).37 Inappropriate line crossing was deter-
mined by video recording. Two groups very sleepy with a
MWT MSL less than 19 minutes and sleepy with a MSL 20
to 33 minutes had significantly more line crossings than
controls and patients with mild sleepiness (MWT MSL
3440 min).
Studies have shown improved performance on driver
simulators after CPAP treatment of OSA.38 In addition,
studies have also shown that the risk of traffic accidents does
appear to be reduced with nasal CPAP therapy (if patients
are compliant).39,40 The evidence for a reduction in motor
vehicle accidents with effective OSA treatment was recently
summarized by Tregear and coworkers40 in a systematic
review with meta-analysis.
ARTERIAL HYPERTENSION
Normal persons and many patients with hypertension but
without sleep apnea have a nocturnal fall in blood pressure.
However, 20% to 40% of patients with OSA fail to have the
normal nocturnal fall in systemic blood pressure (nondip-
pers).41 During obstructive apnea, blood pressure tends to
rise slightly and then to rise abruptly at apnea termination
(Fig. 175) secondary to arousal from sleep and restoration
of breathing associated with sympathetic activation and
parasympathetic withdrawal.
There is continued controversy about whether OSA can
cause daytime (diurnal) as well as nocturnal hypertension.
Animal models of simulated OSA suggest that it can.42
Several studies have found that OSA is very common in adult
populations with hypertension (>30%).43 This association
does not prove causality because patients with hypertension
and OSA share common, potentially causative, factors such
as obesity. Carlson and coworkers44 found that age, obesity,
and sleep apnea were independent and additive risk factors
for the presence of hypertension. The Sleep Heart Health
Study, a large population-based investigation, found an
increased risk of having self-reported hypertension when
OSA was present (Table 172).45
A prospective study of the Wisconsin cohort found an
increase in AHI predicted the development of hypertension
in the following 4 years (increased incidence) after adjusting
for confounding factors such as obesity, age, and smoking
(Table 173).46 In contrast to these findings, a recent analysis
of the Sleep Heart Health data found that there was no rela-
tionship between the AHI and the risk of incident hyperten-
sion (risk of developing hypertension in the next 5 yr) when
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 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment 287

FIGURE 175 This tracing shows the swings in arterial

blood pressure associated with obstructive sleep apnea
200
(respiratory effort tracing not shown). At apnea termination,
there is a steep increase in blood pressure that coincides
Blood
pressure
with increased sympathetic activity. From Berry RB: Sleep
(mm Hg) Medicine Pearls, 2nd ed. Philadelphia: Hanley & Belfus, 2003,
p. 191. Reproduced with permission.
0

20 sec

Airflow

TABLE 172
Cardiovascular Disease and Obstructive Sleep Apnea Sleep Heart Health StudyRisk of Self Reported
Cardiovascular Disease (Prevalence)
QUARTILE
I II III IV P
AHI (#/hr) 01.3 1.44.4 4.511.0 >11.0
CAD* 1.0 0.92 (0.711.20) 1.20 (0.931.54) 1.27 (0.991.62) .004
CHF* 1.0 1.13 (0.542.39) 1.95 (0.993.83) 2.38 (1.224.62) .002
Stroke* 1.0 1.15 (0.721.83) 1.42 (0.912.21) 1.58 (1.022.46) .03
APNEA-HYPOPNEA INDEX CATEGORY
AHI (#/hr) <1.5 1.54.9 514.9 1529.9 30

HTN 1.0 1.07 (0.911.26) 1.20 (1.011.42) 1.25 (1.01.56) 1.37 (1.031.83) .005
CAD = coronary artery disease; CHF = congestive heart failure; HTN = hypertension.
Values are risk (95% confidence interval).
*Data from Shahar E, Whitney CW, Redline S, et al: Sleep-disordered breathing and cardiovascular disease. Am J Respir Crit Care Med 2001;163:1925.

Data from Nieto FJ, Young TB, Lind BK, et al: Association of sleep disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA
2000;283:18291836.

TABLE 173 hypertension. The risk is most significant with severe OSA
Risk of Incident Hypertension in Obstructive Sleep and is confounded by the presence of obesity.
Apnea (Wisconsin CohortPopulation-Based)* Even if sleep apnea does not cause daytime hypertension,
it may well worsen the physiologic impact of the disorder or
QUARTILE
impair treatment efficacy. For example, Verdeechia and
I II III IV P coworkers48 found that hypertensive patients who failed to
AHI (#/hr) 0 0.14.9 5.014.9 >15 have a 10% nocturnal fall in blood pressure had greater LV
hypertrophy. Studies have also documented an increase in
Relative risk 1.0 1.42 2.03 2.89 .002
mortality among nondippers.49 Studies of populations with
(CI) 1.131.78 1.293.17 1.465.64
resistant hypertension have found a high prevalence of
*Based on laboratory measure of blood pressure at baseline versus follow-up
in 4 years (incident HTN).
OSA.50 Therefore, the possibility of the presence of OSA
CI = confidence interval; HTN = hypertension. should be considered in all patients with resistant hyperten-
From Peppard PE, Young T, Palta M, Skatrud J: Prospective study of the sion. One study found that CPAP treatment was helpful in
association between sleep-disordered breathing and hypertension. N Engl J
Med 2000;342:13781384.
patients with resistant hypertension who had OSA.51
If sleep apnea is effectively treated, does hypertension
improve? This question has been approached by a number
of studies that have determined the effect of nasal CPAP on
the risk was adjusted for obesity.47 There was a trend for a nocturnal and daytime blood pressure in patients with OSA.
relationship when the AHI was greater than 30/hr. One Becker and colleagues52 found that effective treatment of
problem with the Sleep Heart Health Study is that the popu- sleep apnea with nasal CPAP for 9 weeks or more lowered
lation contained relatively few patients with severe OSA. In both nocturnal and daytime blood pressure by approxi-
summary, patients with OSA are likely at risk of developing mately 10 mm Hg using a placebo-controlled (sham CPAP)
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288 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
FIGURE 176 A, Time course of mean arterial blood pressure (MAP) 140
before (dark black circles) and on treatment (gray circles) with therapeutic
nasal continuous positive airway pressure (nCPAP). On average, 7.2 hours
were recorded during the night. B, Time course of MAP before (closed 120
circles) and on treatment (open circles) with subtherapeutic nCPAP. Note
MAP (mmHg)
the decreased blood pressure on CPAP but not subtherapeutic CPAP. From
Becker HF, Jerrentrup A, Ploch T, et al: Effect of nasal continuous positive 100
airway pressure treatment on blood pressure in patients with obstructive
sleep apnea. Circulation 2003;107:6873.
80
60
3:15 pm
A
140
120
MAP (mmHg)
100
80
60
3:15 pm
B
study design (Fig. 176). Other investigations have shown
smaller53,54 or no effects on daytime blood pressure.55,56 These
conflicting results may reflect inadequate CPAP treatment
(poor adherence), too short a treatment interval, or less
severe sleep apnea populations.
A meta-analysis of 12 randomized trials of the effect of
CPAP on blood pressure found that CPAP did significantly
reduce 24-hour blood pressure by about 2 mm Hg. Results
were greatest in patients with more severe OSA and better
use of CPAP.57 Of note, ambulatory blood pressure monitor-
ing can cause awakenings and change what it is trying to
measure.58 The study of Becker and colleagues52 used beat-
to-beat blood pressure with a finger probe rather than a
periodically inflating cuff. In general, most hypertensive
patients with sleep apnea will still continue to require anti-
hypertensive medications when treated with CPAP. However,
24-hour control of blood pressure may improve on CPAP
treatment.
PULMONARY HYPERTENSION
Both hypoxemia and acidosis cause constriction of the pul-
monary arteries. Hence, it is not surprising that episodes of
pulmonary hypertension occur during obstructive apnea in
patients with OSA (Fig. 177).59,60 For patients with normal
daytime arterial partial pressure of oxygen (PaO2), the
Baseline
Effective nCPAP Baseline
CPAP
7:15 pm 11:15 pm 3:15 am 7:15 am 11:15 am
Baseline
Subtherapeutic nCPAP
7:15 pm 11:15 pm 3:15 am 7:15 am 11:15 am
pulmonary pressures usually return to normal. Pulmonary
hypertension is often defined as a mean pulmonary artery
pressure greater than 25 mm Hg. The term pulmonary arte-
rial hypertension is reserved for disorders of the pulmonary
arteries that result in pulmonary hypertension. Of note, dia-
stolic dysfunction (high pulmonary venous pressures and LV
end-diastolic pressure) also results in increased pulmonary
arterial pressure. It has been said that OSA patients with
normal daytime blood gases usually have normal or only
mildly increased daytime pulmonary pressures.60,61 The pres-
ence of coexistent chronic obstructive pulmonary disease
(COPD) or LV diastolic dysfunction does appear to increase
the prevalence and severity of daytime pulmonary hyperten-
sion. However, the presence of COPD is not obligatory.61,62
Some OSA patients may have an increased vascular response
to nocturnal episode acidosis and hypoxemia. In the absence
of lung disease or elevated LV end-diastolic pressure, the
incidence of pulmonary hypertension in OSA patients has
been estimated to be 20% to 40%.60 Sajkov and associates62
described a group of patients without OSA with mean pul-
monary pressures up to 26 mm Hg (their normal <20 mm
Hg) and pulmonary systolic pressures up to 40 mm Hg. The
affected group seemed to have a greater increase in pulmo-
nary pressures in response to an increase in cardiac output
or hypoxemia. The authors hypothesized that remodeling of
the pulmonary vascular bed (possibly due to OSA) was
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 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment 289

FIGURE 177 Increase in systolic blood

pressure (SABP) and pulmonary pressure
(PAP) during obstructive apnea. Note the

Poes cmH2O airflow

progressively negative esophageal pressure
Airflow
(Poes). There is cyclic variation in the PAP due to
cycles of negative pressure in the chest, but the
Apnea
overall trend is upward (arrow). Hypoxemia
0 Pes and acidosis (hypercapnia) cause pulmonary
SABP mmHg

200 20 arterial vasoconstriction. SaO2 = arterial oxygen

SABP
saturation; SpO2 = pulse oximetry. From
Podszus T, Greenberg H, Scharf S: Influence of
50
sleep state and sleep disordered breathing on
cardiovascular function. In Sanders NA, Sullivan CE
PAP mmHg

40 (eds): Sleep and Breathing. New York: Marcel

PAP
Decker, 1994, pp. 257310.
0

100
SaO2 %

SpO2
50 10 s

60
P < 0.0001 ARRHYTHMIAS
In normal individuals, the heart rate is lower during NREM
50
sleep than during wakefulness. This is thought to be due to
parasympathetic predominance during sleep.5 In patients
40
with OSA, the heart rate varies in cycles: slowing with apnea
PASP (mmHg)

onset; increasing slightly, staying the same, or decreasing

30
20
10
0 increased vagal tone during apnea is the result of hypoxic
Sham CPAP CPAP
FIGURE 178 A reduction in pulmonary arterial systolic pressure (PASP) (Doppler
Echo) after 3 months of continuous positive airway pressure (CPAP) treatment in CPAP
versus sham CPAP. This was a randomized cross-over trial. From Arias MA, Garca-Ro
F, Alonso-Fernndez A, et al: Pulmonary hypertension in obstructive sleep apnoea: effects
of continuous positive airway pressure: a randomized, controlled cross-over study. Eur
Heart J 2006;27:11061113.
responsible. One long-term case series showed that patients
with OSA and pulmonary hypertension had stable pulmo-
nary pressures over 5 years when treated with CPAP.63
Another study found that CPAP improved pulmonary arte-
rial pressure and vascular reactivity in OSA.64 Alchanatis and
colleagues65 found mild daytime pulmonary hypertension in
a group of OSA patients without lung disease that reversed
after 6 months of CPAP. Arias and associates66 performed a
randomized cross-over trial (sham or effective CPAP) for 12
weeks. CPAP resulted in lower pulmonary arterial systolic
pressure compared with sham (Fig. 178).
during apnea; and increasing dramatically in the postapneic
period6769 (Fig. 179). Early studies attributed the slowing
of heart rate during apnea to increased vagal tone and
hypoxia.67 The slowing was diminished by atropine and sup-
plemental oxygen. Later studies have not consistently found
a reduction in heart rate in the last part of apnea.68,69 The
stimulation of the carotid body during absent ventilation.
With resumption of respiration, inflation of the lungs
decreases vagal tone and the hypoxic influences on sympa-
thetic tone are unmasked (tachycardia). Bonsignore and
coworkers68 found that the heart rate during apnea could
increase, stay the same, or decrease depending on relative
amounts of parasympathetic and sympathetic tone. One
investigation suggested that the individual differences in the
effect of apnea on heart rate may be secondary to differences
in the response of the carotid body to hypoxia.70 Although
the cyclic changes in heart rate are sometimes referred to as
brady-tachycardia, the heart rate often remains between 60
and 90 bpm in most patients.
Guilleminault and colleagues71 reported on 400 patients
with sleep apnea. Forty-eight percent had some type of
arrhythmia. Twenty percent had more than two premature
ventricular contractions (PVCs)/min during sleep, 7% had
severe bradycardia to less than 30 bpm, 3% had nonsus-
tained ventricular tachycardia, and 5% and 3% had Mobitz
type I and type II second-degree block, respectively. Sinus
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290 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
FIGURE 179 Changes in heart rate associated with
obstructive apnea. ECG = electrocardiogram; SaO2 = arterial
oxygen saturation. From Berry RB: Sleep Medicine Pearls,
2nd ed. Philadelphia: Hanley & Belfus, 2003, p. 195.
Airflow
Chest
Abdomen
arrest from 2.5 to 13 seconds was noted in 11%. A prospec-
tive study of 45 recently diagnosed OSA patients used Holter
monitoring for 18 hours after diagnosis and again after 2 to
3 days of CPAP.72 Only 8 of the 45 had significant rhythm
disturbances including ventricular tachycardia, atrial fibril-
lation (Afib), supraventricular tachycardia, and second- or
third-degree heart block. In 7 of these 8 patients, CPAP
resulted in the abolition of rhythm disturbances.
The parasympathetic predominance during apnea in
some patients may have little significance, except in cases of
significant bradycardia or heart block. One study docu-
mented a reversal of atrioventricular conduction block on
CPAP treatment.73 The periods of tachycardia and elevated
blood pressure postapnea increase myocardial oxygen
demand at the same time that hypoxemia exists, predispos-
ing to ischemia and possibly tachyarrhythmias. In normal
individuals, sleep usually is a time of reduced tachyarrhyth-
mias and ischemia. Patients with OSA may not enjoy the
same protection. PVCs are not uncommon in patients with
OSA. However, in some patients, the PVC frequency is actu-
ally lower during sleep. Shepard and associates74 found no
correlation between the SaO2 at desaturation and PVC fre-
quency during sleep unless the SaO2 was less than 60%.
Heart rate variability has been used as a tool to study the
balance of parasympathetic and sympathetic tone in patients
with OSA. During wakefulness, OSA patients show less heart
rate variability than normal individuals. This is thought sec-
ondary to an increase in sympathetic tone that is still present
during the day. After successful treatment with CPAP, the
heart rate variability may increase suggesting a drop in sym-
pathetic activity. Khoo and coworkers75 found that CPAP
treatment of OSA improved vagal heart rate control and that
the degree of improvement varied directly with the amount
of CPAP adherence.
Gami and colleagues76 found that the risk of developing
Afib was more associated with obesity and the degree of
arterial oxygen desaturation than the AHI. Untreated
OSA appears to worsen arrhythmia control. Kanagala and
ECG
85 66 63 67 70 85 92
22 sec
SaO2
80%
associates77 found that patients with untreated OSA had a
higher recurrence of Afib after cardioversion than patients
without a polysomnographic diagnosis of sleep apnea.
Appropriate treatment with CPAP in OSA was associated
with a lower recurrence of Afib. Mehra and coworkers78
evaluated a cohort of older men and found that sleep-
disordered breathing was associated with Afib and complex
ventricular events (CVEs). The prevalence of CVE was asso-
ciated with OSA and hypoxemia whereas Afib was associated
with central sleep apnea (CSA). An evaluation of the Sleep
Heart Health cohort found that, although the rate of arrhyth-
mias was low, the relative risk of Afib or nonsustained ven-
tricular tachycardia was much higher following respiratory
events.79 In Figure 1710, a patient with OSA changes from
sinus rhythm to Afib after apnea termination. Ryan and
coworkers80 performed a randomized, controlled trial of
CPAP in heart failure patients to determine whether ven-
tricular premature beats (VPBs) would decrease. The study
found that CPAP did reduce VPB frequency (58% reduction)
during sleep. The urinary norepinephrine concentration also
decreased. No changes were noted in the control group.80
CORONARY ARTERY DISEASE
The Sleep Heart Health Study of a large prospective cohort
of patients found evidence of a slight increase in risk of
having self-reported coronary artery disease (CAD) at even
low levels of sleep apnea (prevalence) (see Table 172).81
Peker and colleagues82 found an increase in mortality in
patients with CAD who had untreated OSA. Gottlieb and
associates83 evaluated the Sleep Heart Health cohort data and
found an increased risk of incident CAD was associated with
the presence of OSA in men younger than 70 years of age.
The association was strongest for severe OSA. Milleron and
coworkers84 found CPAP treatment of patients with OSA and
CAD improved event-free survival (Fig. 1711). The end
point was a composite of cardiovascular death, acute coro-
nary syndrome, hospitalization for CHF, or need for
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 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment 291

A
ECG

NP

NO airflow

Chest

Abdomen

SpO2
96%
85%

FIGURE 1710 A patient with sleep apnea in sinus rhythm develops atrial fibrillation after termination of an obstructive apnea. A blow-up of area A is
shown in the lower left corner. NO airflow = nasal oral thermal flow; NP = nasal pressure; SpO2 = pulse oximetry. The tracing is 60 seconds in duration.

TABLE 174
1 Effect of Obstructive Sleep Apnea on Factors
Contributing to Atherosclerosis and Thrombosis
0.8
IMPROVED
Event-free survival

UNTREATED OSA WITH CPAP

0.6
Increased am hematocritKreiger, Less natriuresis
0.4 199085
Increased fibrinogenChin, 199686 Yes86
0.2
Neutrophil activation89 Yes89
Treated group P < 0.01
0 Untreated group Increased visceral fat97 Decreased
visceral fat97
0 10 20 30 40 50 60
Time (months) Platelet activationBokinsky, 199590 Yes90

FIGURE 1711 Patients with coronary artery disease (CAD) and OSA. Those treated VEGFLavie, 200287 Yes87
with CPAP had improved survival compared with untreated patients. From Milleron O, Reactive oxygen species Yes88
Pillire R, Foucher A, et al: Benefits of obstructive sleep apnoea treatment in coronary Dyugovskaya, 200288
artery disease: a long-term follow-up study. Eur Heart J 2004;25:728734.
Superoxide releaseSchulz, 200089 Yes89
Elevated C-reactive protein9193 Yes93
coronary revascularization. The control group was patients
Elevated IL-691 Yes91
who declined CPAP (not a randomized trial). The mean
follow-up was 86 months. Elevated TNF-alpha, IL-894 Yes94
CPAP = continuous positive airway pressure; IL = interleukin; OSA =
obstructive sleep apnea; TNF-alpha = tumor necrosis factor-alpha; VEGF =
ATHEROSCLEROSIS AND THROMBOSIS vascular endothelial growth factor.

There have also been a growing number of studies showing

changes in blood components or indicators of inflammation
in OSA that may be associated with an increased risk of
atherosclerosis or thrombosis (Table 174). In OSA, there is
an increase in the early morning hematocrit85 and fibrinogen
levels86 that decrease after CPAP treatment. The levels of
vascular endothelial growth factor (VEGF),87 extent of neu-
trophil,88,89 and platelet activation90 are also reduced with
CPAP treatment of patients with OSA. Inflammation is now
believed to play a role in atherosclerosis or plaque rupture.
The level of C-reactive protein (a marker of inflammation)
is reduced with CPAP treatment.9193 Intermittent hypoxia
(hypoxia-reoxygenation) is believed to selectively activate
several inflammatory pathways.94 For example, tumor
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292 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
necrosis factor-alpha (TNF-alpha) and interleukin-8 (IL-8)
are elevated in untreated OSA but decrease with CPAP treat-
ment.95 TNF-alpha can also cause daytime sleepiness. In this
study, higher TNF-alpha levels were associated with higher
Epworth Sleepiness Scale scores and worsened arterial
oxygen desaturation. Other studies found a reduction in
leptin96 (a hormone secreted by adipose tissue) and a reduc-
tion in visceral fat97 on CPAP treatment. Increased visceral
fat is associated with an increased risk of cardiac disease. Of
note, not all studies have found an association between OSA
and leptin that is independent of the degree of obesity. In
some studies, increased leptin levels were associated with the
degree of obesity rather than with the AHI.98 Endothelial
function is impaired (specifically NO-dependent flow-
mediated dilatation) in patients with OSA, and studies
suggest improvement after CPAP.99
In studies comparing OSA patients with normal subjects,
using an appropriate control group is essential. For example,
it is often difficult to match groups for obesity. Trials of the
effects of CPAP do not require a normal control group.
However, many of the previously discussed studies of effects
of CPAP on inflammatory changes in OSA patients were not
randomized, controlled trials. Therefore, the results need to
be confirmed by controlled trials. For example, a recent ran-
domized, controlled trial of CPAP found no change in several
inflammatory mediators following 4 weeks of CPAP.100
Another study found decreases in C-reactive protein after
CPAP treatment only in those patients with good CPAP
compliance and with elevated C-reactive protein levels at
baseline.93 Therefore, results may vary depending on the
characteristics of the patients at baseline and the compliance
with CPAP treatment.
CONGESTIVE HEART FAILURE
The Sleep Heart Health study found that the presence of OSA
increases the risk of having CHF (see Table 172).81 Con-
versely, studies have suggested that sleep-disordered breath-
ing is common in patients with CHF.101,102 One should not
assume that complaints of disturbed nocturnal sleep are
simply secondary to heart failure. Sin and colleagues103 ret-
rospectively evaluated a group of patients with significant LV
failure referred to the sleep laboratory and found that risk
factors for OSA included an increased BMI for men and
increased age for women. In patients with CHF and OSA,
negative intrathoracic pressure, hypoxemia, and increased
sympathetic tone associated with the apneas are believed to
negatively affect ventricular function.5,103 Treatment of OSA
with nasal CPAP in patients with CHF has been found to
improve the ejection fraction and symptoms in a number of
studies.104106 This appears to occur because of a reduction in
sympathetic tone and a decrease in ventricular afterload.103
However, all studies have not shown a significant benefit.107
To date, no study has confirmed a reduction in mortality
with CPAP treatment.
Patients with CHF may manifest Cheyne-Stokes breath-
ing (CSB) type of CSA (see Chapter 21). Short-term studies
showed that CPAP improved the ejection fraction in
CSB-CSA patients,108,109 and one study suggested that there
may be a survival advantage if patients with CHF and
CSB-CSA were treated with CPAP.109 However, a large ran-
domized trial of CPAP versus standard care in patients with
CSB-CSA was unable to show a survival benefit.110 However,
only roughly 50% of the patients in this study responded to
CPAP. An analysis of the subgroup that responded to CPAP
did have a survival advantage (a post-hoc analysis).111 The
reasons CPAP treatment improves CSA102 are unclear but
could include beneficial effects on hemodynamics (decreased
afterload), reduction in pulmonary wedge pressure (may
reduce ventilatory drive), or induction of mild increases in
PCO2. The latter two possibilities might stabilize ventilatory
control (see Chaper 21). Adaptive servoventilation (ASV)
has been more successful than CPAP in acutely reducing the
AHI in patients with CSB-CSA and benefits in cardiac func-
tion have been shown.112115 However, no study has shown
that ASV treatment improves survival.
CEREBROVASCULAR ACCIDENTS AND OSA
A number of studies have shown a high prevalence of sleep-
disordered breathing in patients soon after a cerebrovascular
accident (CVA).116,117 Although the predominant form of
sleep-disordered breathing is OSA, CSA with CSB can also
occur.11,118 The CSB-CSA is believed to occur early in the
post-CVA period and then usually resolves. In contrast, OSA
seems to persist after a CVA. However, the temporal relation-
ship between OSA and stroke is not well defined. It is not
known whether brain damage from CVA causes sleep apnea
or if sleep apnea preceded the stroke. If so, is the presence of
sleep apnea an independent risk factor for the development
of a CVA? The Sleep Heart Health Study showed an increased
risk of having a self-reported CVA (prevalence) if OSA is
present (see Table 172).81 In a recently published study,
Redline and associates119 evaluated the Sleep Heart Health
data and found an increased risk for incident ischemic
stroke in men with mild to moderate OSA. In this study, data
were adjusted for a number of confounders that complicated
the analysis including obesity. If there is a causal role for OSA
in stroke, what are the mechanisms? As noted previously,
OSA may predispose to atherosclerosis, hypertension, and
early morning hemoconcentration. These factors increase
the risk of stroke. During sleep apnea, there are increases in
intracranial pressure (ICP)120 and decreases in cerebral blood
flow.121 There is an increase in ICP with each apneic event
and the rise tends to be correlated with the length of apnea.
The increase in ICP is thought to be secondary to increases
in central venous pressure, systemic pressure, and cerebral
vasodilatation from increases in PaCO2 during respiratory
events. Because cerebral perfusion is proportional to the
mean arterial pressure (MAP) ICP, increases in ICP may
reduce perfusion pressure even if MAP also rises. Studies of
cerebral blood flow velocity using Doppler monitoring have
shown that flow velocity increases in early apnea, then has
approximately a 25% fall below baseline at end apnea.121
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 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
There is some evidence that the presence of OSA in
patients who have suffered a CVA is a bad prognostic sign
regardless of whether OSA precedes or follows the CVA.
Good and coworkers122 found that the Barthel index (a mul-
tifaced scale measuring mobility and activities of daily living
that is used to assess patients after stroke) was significantly
lower in patients with OSA and CVA compared with those
with no evidence of OSA after CVA. The presence of OSA
was determined at discharge and the Barthel index was lower
at 3 and 12 months in the OSA-CVA group. Martinez-Garcia
and colleagues123 found that CPAP treatment reduced the
mortality after ischemic stroke in patients with concomitant
OSA. However, adherence to CPAP in patients with a recent
CVA tends to be low.
ERECTILE DYSFUNCTION
An association between erectile dysfunction and sleep dis-
orders appears to exist in survey studies relying on self-
report and in small case series.124 Hormonal, neural, and
endothelial mechanisms have been implicated in linking
sleep disorders with erectile dysfunction. Treatment of sleep
disorders, specifically sleep apnea with CPAP, has been
shown to improve patient erectile function.125
DIABETES
Obesity is a major confounding factor in the analysis of the
association between diabetes mellitus (DM) and OSA
because both are worsened with increased BMI. Studies have
found that obese and nonobese patients have abnormal
glucose metabolism related to OSA. Punjabi and Beamer126
found that independent of adiposity, sleep-disordered
breathing was associated with impairment of insulin sensi-
tivity, glucose effectiveness, and pancreatic beta cell func-
tion. Harsch and associates127 found that CPAP rapidly
improved insulin sensitivity, although the greatest results
were in nonobese patients. Babu and coworkers128 found that
in diabetic OSA patients with a hemoglobin A1c greater than
7%, CPAP treatment reduced the A1c. Lam and colleagues129
compared sham CPAP and effective CPAP in patients with
OSA and found that 1 week of CPAP improved insulin sen-
sitivity in nondiabetic males, and the improvement was
maintained for 12 weeks of treatment in those with moderate
obesity. Conversely, West and associates130 were not able to
show an improvement in insulin resistance with CPAP treat-
ment. Although these studies do suggest that OSA indepen-
dent of obesity impairs glucose metabolism, the effect may
be more pronounced in nonobese patients. The impact of
treatment of OSA on long-term diabetes and the diabetic
complications remains to be determined.
NOCTURIA
It has been a common clinical observation that many patients
with OSA who start CPAP treatment report fewer awaken-
ings to urinate. Hajduk and coworkers131 found a high inci-
dence of pathologic nocturia (PN; defined as 2 urination
293
events/night) in OSA patients. The percentage of PN was
47.8% and age, arousal index, AHI, and measures of oxygen-
ation were predictors of the presence of PN. Some of the
reported effect of CPAP treatment could be due to better
sleep. However, studies have shown a reduced sodium excre-
tion in OSA patients treated with CPAP. Krieger and col-
leagues132 found that OSA patients had greater urinary flows
and greater urinary sodium excretion compared with con-
trols. Nasal CPAP resulted in a reduction in urinary flow and
sodium and chloride excretion. A second study by the same
group found evidence of increased guanosine 35-cyclic
monophosphate excretion in untreated OSA patients, which
reflects atrial natriuretic peptide (ANP) release. The authors
hypothesized that atrial stretch during sleep apnea induced
release of ANP, which caused increased sodium excretion.133
Umlauf and associates134 also found increased nocturia and
elevated urinary ANP when the AHI was greater than or
equal to 15/hr. Fitzgerald and coworkers135 found that CPAP
decreased nocturia in OSA patients.
CONSEQUENCES OF CHILDHOOD OSA
Many of the important consequences of untreated pediatric
OSA are listed in Table 175.136 They are divided into neu-
robehavioral, metabolic, and cardiovascular groups.
TABLE 175
Sequelae of Pediatric Obstructive Sleep Apnea
NEUROCOGNITIVE
Decreased quality of life
Aggressive behavior
Poor school performance
Depression
Attention deficit
Hyperactivity
Moodiness
METABOLIC
Elevated C-reactive protein
Insulin resistance
Hypercholesterolemia
Elevated transaminases
Decreased insulin-like growth factor
Decreased/altered growth hormone secretion
Increased leptin
CARDIOVASCULAR
Autonomic dysfunction
Systemic hypertension
Absent blood pressure dipping during sleep
Left ventricular dysfunction
Pulmonary hypertension
Abnormal heart rate variability
Elevated vascular endothelial growth factor
From Katz E, Ambrosio CM: Pediatric obstructive sleep apnea. Clin Chest Med
2010;31:221.
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294 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
Neurobehavioral
Studies have suggested that both habitual snoring and child-
hood OSA are associated with behavioral problems, particu-
larly hyperactivity and inattentive behaviors.136139 These may
improve after effective treatment (usually with tonsillectomy
and adenoidectomy). Sometimes, a diagnosis of attention-
deficit disorder is made when a patient actually has OSA.
Conversely, one should not assume every child with atten-
tion deficit disorder and hyperactivity (ADHD) has OSA.
Children with OSA often have poor school performance and
performance on tests of intelligence that improve with treat-
ment. Both hypoxia and sleep fragmentation may cause neu-
rocognitive changes. Although studies suggest that most
impairment is reversible with treatment, it is still not known
whether an irreversible component of central nervous system
damage occurs with untreated OSA. Although excessive
daytime sleepiness is less prominent in childhood OSA com-
pared with OSA in adults, it does occur and may be unrec-
ognized. Using the MSLT, daytime sleepiness is thought to
occur in between 13% and 40% of patients.136,140 Daytime
sleepiness is often more prominent in obese children with
pediatric OSA.
Metabolic and Inflammatory Consequences
Untreated pediatric OSA has been associated with a failure
to thrive.136,141,142 The possible origin is a reduction in insulin-
like growth factor (IGF) and growth hormone secretion.
IGF-binding protein (IGF-3) correlates with growth hormone
secretion and is decreased in some children with OSA. These
changes are reversible and catch-up growth occurs with
adequate treatment. Today with the obesity epidemic, obesity
is more often noted than failure to thrive. Up to one half of
childhood OSA patients have obesity.143 Leptin, an adipocyte-
secreted hormone, is increased in children with OSA and
decreases after treatment.144,145
Leukotrienes and their receptors are increased in adeno-
tonsillar tissue and exhaled condensates of children with
OSA.146,147 The combination of nasal inhaled steroid and the
leukotriene inhibitors (montelukast) was found to have
benefit in a study of patients with residual sleepiness after
tonsillectomy and adenoidectomy.148 However, long-term
success with anti-inflammatory therapy has not been estab-
lished. Children with OSA may also have elevated serum
levels of TNF-alpha, C-reactive protein, IL-6 and IL-8, and
interferon-gamma levels.136 These changes can occur inde-
pendent of obesity.
Cardiovascular Consequences
Children with OSA have similar cardiovascular conse-
quences as adults but changes occur at the much lower AHI
values typical in children.136 Children with severe OSA
(AHI > 10/hr) may have lack of nocturnal blood pressure
dipping and high AM blood pressure. In severe cases, RV and
LV hypertrophy have been described.
CLINICAL REVIEW QUESTIONS
1. OSA is associated with all of the following EXCEPT:
A. Increased daytime sympathetic tone.
B. Increased heart rate variability.
C. Endothelial dysfunction.
D. Increased nocturnal sodium excretion.
2. During sleep, patients with OSA experience:
A. Decreased venous return.
B. Negative intrathoracic pressure.
C. Decreased systemic afterload.
D. Parasympathetic predominance.
3. All of the following are associated with increased mortal-
ity in OSA EXCEPT:
A. Severe arterial oxygen desaturation.
B. Age > 70 years.
C. Severe versus mild OSA.
D. Co-morbid conditions (DM, CHF, COPD).
4. All of the following are true concerning patients with a
recent stroke who are found to have sleep apnea EXCEPT:
A. CSA is more common than OSA.
B. Worse prognosis.
C. Improved prognosis with CPAP treatment.
D. Low adherence to CPAP treatment.
5. Untreated OSA is associated with all of the following
EXCEPT:
A. Decreased leptin.
B. Increased C-reactive protein.
C. Increased AM hematocrit.
D. Increased VEGF.
Answers
1. B. Untreated OSA is associated with decreased heart rate
variability. This is thought to be due to higher sympa-
thetic compared with parasympathetic tone.
2. B. Due to negative intrathoracic pressure there is increased
venous return and increased systemic afterload. Sympa-
thetic tone is increased during sleep compared to normal
individuals.
3. B. Most of the available evidence suggests an increased
risk for middle-aged rather than older (age > 70 years)
patients.
4. A. Although both OSA and CSA can occurs after stroke,
OSA is much more common. Studies suggest that the
presence of sleep apnea is associated with a worse progno-
sis and that CPAP treatment improves outcome. However,
adherence with CPAP treatment is problematic.
5. A. Some studies have shown an increase in leptin with
untreated OSA, whereas other studies have suggested this
finding is more related to obesity than to OSA.
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 Chapter 17 Consequences of Obstructive Sleep Apnea and the Benefits of Treatment
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2008;15:100106.
139. Capdevila OS, Kheirandish-Gozal L, Dayyat E, Gozal D: Pedi-
atric obstructive sleep apnea: complications, management,
and long-term outcomes. Proc Am Thorac Soc 2008;5:
274282.
140. Gozal D, Kheirandish-Gozal L: Obesity and excessive daytime
sleepiness in prepubertal children with obstructive sleep
apnea. Pediatrics 2009;123:1318.
141. Guilleminault C, Eldridge FL, Simmons FB, et al: Sleep apnea
in eight children. Pediatrics 1976;58:2330.
142. Brouillette RT, Fernbach SK, Hunt CE: Obstructive sleep
apnea in infants and children. J Pediatr 1982;100:3140.
143. Gozal D, Simakajornboon N, Holbrook CR, et al: Secular
trends in obesity and parentally-reported daytime sleepiness
among children referred to a pediatric sleep center for snoring
and suspected sleep-disordered breathing (SDB). Sleep
2006;29:A74.
144. Tauman R, Serpero LD, Capdevila OS, et al: Adipokines in
children with sleep disordered breathing. Sleep 2007;30:
443449.
145. Nakra N, Bhargava S, Dzuira J, et al: Sleep-disordered breath-
ing in children with metabolic syndrome: the role of leptin
and sympathetic nervous system activity and the effect of
continuous positive airway pressure. Pediatrics 2008;122:
e634e642.
146. Goldbart AD, Goldman JL, Li RC, et al: Differential expres-
sion of cysteinyl leukotriene receptors 1 and 2 in tonsils of
children with obstructive sleep apnea syndrome or recurrent
infection. Chest 2004;12:613618.
147. Goldbart AD, Krishna J, Li RC, et al: Inflammatory mediators
in exhaled condensate of children with obstructive sleep
apnea syndrome. Chest 2006;130:143148.
148. Kheirandish L, Goldbart AD, Gozal D: Intranasal steroids and
oral leukotriene modifier therapy in residual sleep-disordered
breathing after tonsillectomy and adenoidectomy in children.
Pediatrics 2006;117:e61e66.
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Obstructive Sleep Apnea
Treatment Overview and
Medical Treatments
Chapter Points
The choice of treatment for OSA depends on OSA
severity, symptoms, co-morbid medical conditions,
patient preference, and sometimes economic
issues.
Treatment options for snoring included the side sleep
position, treatment of nasal congestion, weight loss
(adjunctive), an OA, or upper airway surgery.
Treatment options for mild OSA include the side sleep
position, treatment of nasal congestion, weight loss
(adjunctive), an OA, or upper airway surgery. If the
patient is symptomatic, PAP treatment can also be
effective if the patient is motivated.
Treatment options for moderate OSA include PAP
(treatment of choice), an OA, or upper airway surgery.
Weight loss or the side sleep position is adjunctive.
Treatment options for severe OSA include PAP
(treatment of choice), upper airway surgery such as
the MMA (if anatomy is favorable and the patient is a
good surgical candidate), or an OA (third option).
Mild to moderate weight loss can reduce the AHI, but
weight loss takes time and is considered adjunctive
therapy.
Bariatric surgery resulting in weight loss can reduce
the AHI. However, a substantial fraction of patients
with presurgery OSA continue to need treatment after
weight loss stabilizes. In some patients, the required
level of CPAP is lower. OSA can return even in the
absence of weight gain.
Positional therapy can be effective in patients with
positional OSA, but long-term studies of effectiveness
are lacking. Sleep in the lateral position or with the
head elevated can reduce the level of CPAP required to
keep the airway open.
Modafinil (armodafinil) is indicated for treatment of
residual excessive daytime sleepiness in patients with
OSA on effective CPAP treatment (good adherence and
Chapter 18
effective pressure) when other sleep disorders have
been ruled out. Continued monitoring of PAP
adherence is essential.
The AASM practice parameters state that supplemental
oxygen treatment is not indicated for treatment of
OSA. However, individual patients may benefit if they
do not tolerate or do refuse more effective treatment.
Oxygen treatment can increase event duration.
Significant worsening of nocturnal and daytime
hypercapnia can occur in some patients with the use
of supplemental oxygen.
INTRODUCTION
The severity of obstructive sleep apnea (OSA), co-morbid
conditions, patient preference, and financial considerations
may all factor into the choice of treatment modality16 (Table
181). The American Academy of Sleep Medicine (AASM)
has published practice parameters for medical,3 surgical,4
oral appliance (OA),5 and positive airway pressure (PAP)6
treatments for sleep apnea. Medical treatments for OSA are
discussed in this chapter. Treatment of OSA with PAP is
discussed in detail in Chapter 19 and OA and surgical treat-
ment of OSA are covered in Chapter 20. Although treatment
options for OSA are usually classified by apnea-hypopnea
index (AHI) severity, symptoms do not correlate well with
the AHI. Therefore, the goal should be treat the patient, not
the AHI. Another concept to consider is efficacy versus
effectiveness. For example, continuous positive airway pres-
sure (CPAP) is very efficacious, often lowering the AHI to
less than 5 to 10/hr. However, the effectiveness of CPAP
depends on adherence to treatment. If CPAP reduces the
AHI from 55 to 5/hr but is used only 50% of the time during
sleep, the effective average AHI is really 30/hr. The ideal OSA
treatment goals include normalization of the AHI and noc-
turnal oxygenation and resolution of symptoms associated
with OSA.
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300 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments
TABLE 181
Treatment Alternatives for Obstructive Sleep Apnea (Adults)46
SNORING MILD
Primary Treat nasal congestion Oral appliance
or
Lateral positioning Upper airway surgery
Secondary Oral appliance PAP (if symptomatic)
or
Upper airway surgery
Adjunctive Weight loss Weight loss
Lateral positioning
PAP = positive airway pressure.
SHOULD MILD OSA PATIENTS BE TREATED?
Whereas most clinicians recommend treatment of patients
with an AHI of 15/hr or greater even if not symptomatic,
treatment of mild OSA remains controversial.7,8 However,
there can be night-to-night variability in the AHI and even
patients with mild OSA can be symptomatic. In the Sleep
Heart Health Study, 28% of individuals with an AHI greater
than 5 but less than 15 had subjective sleepiness (Epworth
Sleepiness Scale [ESS] 11).9 The Wisconsin cohort study
found a 2.03 greater risk of incident hypertension in patients
with an AHI in the range of 5 to 14.9 compared with indi-
viduals without sleep apnea (AHI = 0/hr).10 The fact that
even mild OSA could have adverse consequences is sup-
ported by a recent finding that snoring alone can cause
carotid atherosclerosis.11 Effective treatment of patients with
mild OSA can improve symptoms. A meta-analysis of treat-
ment studies of mild to moderate OSA found that CPAP
significantly reduced subjective sleepiness (the ESS decreased
by 1.2 points) and improved objective wakefulness (measure
of wakefulness test [MWT] sleep latency increased by
2.1 min).12 Conversely, Barb and coworkers13 found no
benefit to CPAP treatment in a group of nonsleepy patients
with mild to moderate OSA. Whereas suboptimal CPAP
adherence has often been reported in studies of patients with
mild OSA, several studies found 40% to 60% of patients had
greater than 4 hours use for 70% of nights.7
WHOM TO TREAT
At least four treatment considerations affect the decision to
treat a patient with OSA. The first category is the severity of
OSA as based on the AHI or extent of arterial oxygen desatu-
ration. The second consideration is presence or absence of
symptoms. Symptomatic OSA should always be treated but
the choice of treatment may vary, as noted later. The third
consideration is the impact of OSA on the sleep of the
patients bed partner. Loud snoring and apnea may cause
marital discord and impair the sleep of the patients bed
partner.14 In some cases, sleeping in separate bedrooms is the
most acceptable solution. However, if this is not acceptable,
MODERATE SEVERE
PAP PAP
Oral appliance Upper airway surgery
or or
Upper airway surgery Oral appliance
Weight loss Weight loss
Lateral positioning Lateral positioning
treatment of the OSA patient can significantly improve the
sleep of the bed partner.14 The fourth category is the increased
risk of adverse cardiovascular morbidity and mortality asso-
ciated with untreated sleep apnea. The evidence that
untreated sleep apnea is associated with an increased risk of
death or adverse cardiovascular event is strongest for severe
OSA (AHI > 30/hr) and in men who are 40 to 70 years of
age.15,16 The evidence is less clear for moderate OSA and for
women. However, the presence of certain co-morbid condi-
tions such as coronary artery disease, cerebrovascular
disease, arrhythmias, or congestive heart failure may increase
the risk even for milder degrees of sleep apnea.17 Given that
PAP treatment is safe and effective, treatment of patients
with moderate OSA is recommended even if patients are
asymptomatic.
Table 182 illustrates an approach to the decision of
whom to treat. Symptomatic patients with all severities of
OSA should be treated with an effective therapy. Asymptom-
atic patients with moderate to severe OSA should also be
treated. For asymptomatic patients with mild OSA and no
obvious significant medical co-morbidities, either observa-
tion or conservative treatment (weight loss/lateral position-
ing) is reasonable. The patient should be informed that even
mild OSA carries some increased risk of cardiovascular mor-
bidity. For asymptomatic patients with mild OSA and sig-
nificant medical co-morbidities, treatment decisions
should be individualized based on the patients motivation
to undergo treatment. Treatment success in asymptomatic
patients with mild OSA requires them to be motivated.
TREATMENT SELECTION
Treatment options for snoring, mild, moderate, and severe
OSA are discussed in detail in the following sections. The
options by category of AHI severity are listed in Table
181.
Snoring
For snoring patients for whom treatment is felt necessary, a
number of therapies are available including weight loss,
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 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments
TABLE 182
ConsiderationWhom to Treat?
SYMPTOMATIC ASYMPTOMATIC
AHI No significant medical morbidities
Mild Treat Observation or conservative treatment
Moderate Treat Treat
Severe Treat Treat
Conservative treatment: weight loss, side sleep position, treat nasal congestion, avoid alcohol.
AHI = apnea-hypopnea index.
medical treatment of nasal congestion, the side (lateral)
sleeping position, and avoidance of alcohol. If medical treat-
ment does not improve nasal congestion, nasal surgery may
address this problem, although improvement in snoring is
variable.18,19 OAs or upper airway surgery involving the
palate may improve snoring in many patients.6,2025 The sur-
gical procedures commonly used for snoring include
laser-assisted uvulopalatoplasty (LAUP), radiofrequency
palatoplasty, and uvulopalatopharyngoplasty (UPPP).2123
The Pillar procedure involves insertion of Teflon strips into
the palate. The success of this procedure is variable, and
sometimes additional strip insertion is needed.22 A con-
trolled study comparing the Pillar procedure with a sham
surgery found modest improvement in snoring without a
significant improvement in the AHI.23 The LAUP procedure
is not recommended for treatment of sleep apnea.24 The
recently published American Academy of Sleep Medicine
(AASM) practice parameters for surgical treatment of OSA4
state palatal implants may be effective in some patients with
mild OSA who cannot tolerate or are unwilling to adhere to
PAP therapy, or in whom oral appliances have been consid-
ered and found ineffective or undesirable. However, the
evidence to support this recommendation is not very con-
vincing and it is not clear that palatal implants are any more
effective for sleep apnea than the LAUP procedure.
Mild OSA
For mild OSA, one may again begin with conservative mea-
sures in (especially in asymptomatic patients) including
treatment of nasal congestion, weight loss, or the lateral
sleeping position. Weight loss takes time, and if the patient
is symptomatic, weight loss should be considered a second-
ary (adjunctive) treatment.3 Both OAs and upper airway
surgery are reasonably effective for mild OSA.4,5,2025 PAP is
very efficacious at reducing the AHI,1,2,6 but acceptance and
adherence are typically lower than with more severe OSA.
PAP treatment is not indicated in mild OSA if patients are
asymptomatic and have no co-morbid cardiovascular dis-
orders.2 In symptomatic patients with mild OSA, some
patients may prefer a trial of PAP rather than an OA or upper
airway surgery. PAP treatment is safe and it is often difficult
to predict who will benefit. If the patient is motivated to try
301
ASYMPTOMATIC
Significant medical morbidities
? Treat
Treat
Treat
PAP, the dictum when in doubt, pressurize the snout
should be considered.26 If PAP is not an acceptable option,
the choice between upper airway surgery or an OA to treat
mild OSA often depends upon financial considerations and
patient preference. At the present time, many insurance
plans will not pay for OA treatment for sleep apnea. However,
OA treatment is now reimbursed by Medicare if certain con-
ditions are met (see Chapter 20). Reimbursement by insur-
ance or Medicare requires that patients with mild OSA be
symptomatic.
Moderate OSA
For moderate OSA, the treatment of choice is some form of
PAP.1,2,5 For moderate OSA, OA treatment and upper airway
surgery are less reliable than PAP at reducing the AHI to less
than 10/hr. However, they may be more acceptable to some
patients and more effective if patients do not have reason-
able PAP adherence.1,5,20,21 Upper airway surgery obviates the
need for treatment adherence. Treatment adherence is still
an issue with OA treatment, and currently, there is no
method to objectively monitor adherence to OA treatment.
A recent AASM task force review concluded that OA was
about 50% effective for moderate OSA (defined as a treat-
ment AHI < 10/hr).20 A meta-analysis of surgery in OSA
patients concluded that palatal surgery with or without
genioglossus advancement was approximately 30% effective,
using a strict outcome measure of reduction in the AHI to
less than 10/hr.25 Therefore, for moderate OSA, PAP is the
most reliably efficacious treatment. It is very effective if
adherence is adequate. Most clinicians would recommend a
trial of PAP therapy for patients with moderate OSA. If this
treatment is not acceptable or the patient is not adherent to
PAP treatment, upper airway surgery or an OA would be
alternatives.
The AASM practice parameters for the surgical treatment
of OSA4 state Uvulopalatopharyngoplasty (UPPP) as a sole
procedure, with or without tonsillectomy, does not reliably
normalize the AHI when treating moderate to severe OSA.
Therefore, patients with severe OSA should initially be
offered PAP therapy, while those with moderate OSA should
initially be offered either PAP therapy or oral appliances.
However, economics or patient preference may favor surgery
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302 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments

over OA treatment in some settings. If patients with moder- for ultimate recommendations, involving the patient and
ate OSA pursue weight loss with bariatric surgery, an effec- spouse in decision making is essential to improve treatment
tive immediate treatment for OSA is indicated because outcomes. Drowsy driving counseling should be performed
weight loss takes time. and documented. Many patients have co-morbid conditions
such as depression, insomnia, restless legs syndrome (RLS),
or chronic pain that will make compliance with PAP or other
Severe OSA
treatments more difficult. These should be evaluated and
For severe OSA, PAP is the treatment of choice because of treated.
its effectiveness and safety.1,2,6 Unfortunately, acceptance and
adherence can be as low as 50% depending on the definition
FOLLOW-UP AND OUTCOMES ASSESSMENT
of adherence. The maxillary mandibular advancement
(MMA) operation can result in acceptable residual AHIs in Following treatment initiation, careful follow-up is essential
many patients with severe OSA.4,21 A recent meta-analysis because OSA is a chronic disease. Table 185 lists some
found that up to 90% of patients undergoing MMA had
improvement in symptoms and a postoperative AHI less
than 20/hr (only 30% had a reduction in AHI to < 10/hr)25 TABLE 184
(Table 183). Some surgeons perform MMA only after other Patient Education and Co-morbid Disorders
surgical procedures have failed. However, in very obese
PATIENT EDUCATION
patients with retrognathia, performing MMA as the first sur-
gical procedure is recommended by some clinicians. Trache- Testing resultsdiscuss with the patient without
ostomy is effective when life-threatening OSA and respiratory excessive medical jargon, answer questions
failure are present and the patient is not compliant with PAP Pathophysiology of OSA
treatment.4 Surgical treatment options are discussed in more
Consequences of untreated OSA
detail in Chapter 20. If neither PAP nor surgery is an accept-
able treatment option, some patients with severe OSA will Treatment optionspros and cons
have significant improvement in the AHI with OA treat- Drowsy driving counseling
ment. Although the AHI is usually not reduced below 10/hr,
one could argue that a drop from 80/hr to 20/hr is worth- EVALUATION AND TREATMENT OF CO-MORBID DISORDERS
while, especially if there is symptomatic improvement and RLS
an improvement in oxygenation. Depression
Insomnia
PATIENT EDUCATION BEFORE TREATMENT
Insufficient sleep
Following polysomnography (PSG) or portable monitoring
Chronic pain
(home sleep testing, limited-channel sleep testing), the phy-
sician ordering the study should discuss the findings and the Narcolepsy
consequences of untreated sleep apnea with the patient OSA = obstructive sleep apnea; RLS = restless legs syndrome.
(Table 184).1 The factors that can exacerbate OSA, includ-
ing weight gain, insufficient sleep, medications, and alcohol
consumption, should also be addressed. The available treat-
TABLE 185
ment options and the pros and cons of each option should
Assessments for Treatment Follow-up
be discussed. Whereas most patients look to the physician
ASSESSMENTS

TABLE 183 Objective adherence

Meta-Analysis Results for Upper Airway Surgery Epworth Sleepiness Scale, resolution of sleepiness
(% Success Rates)
Quality of life
50% REDUCTION
Patient and spousal satisfaction
CRITERIA IN AHI TO 20/HR AHI < 10/HR AHI < 5/HR
COUNSELING
Phase I 55% 31.5% 13%
Increased adherence
Phase II 86% 45% 43%
Phase I = uvulopalatoplasty with or without genioglossus advancement and
Proper maintenance of equipment
hyoid advancement; Phase II = MMA. Avoidance of factors worsening disease
AHI = apnea-hypopnea index; MMA = maxillary-mandibular advancement.
From Elshaug AG, Moss JR, Southcott A, et al: Redefining success in airway Weight loss
surgery for obstructive sleep apnea: a meta-analysis and synthesis of the
evidence. Sleep 2007;30:461467. Adequate amount of sleep
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 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments 303

TABLE 186
American Academy of Sleep Medicine Practice Parameter Recommendations for Medical Treatment of
Obstructive Sleep Apnea
WEIGHT REDUCTION
Successful dietary weight loss may improve the AHI in obese OSA patients. (Guideline)
Dietary weight loss should be combined with primary treatment of OSA. (Option)
Bariatric surgery may be adjunctive in treatment of OSA in obese patients. (Option)
POSITIONAL THERAPIES
Positional therapy, consisting of a method that keeps the patient in a nonsupine position, is an effective secondary therapy or
can be a supplement to primary therapies for OSA in patients who have a low AHI in the nonsupine versus the supine
position. (Guideline)
OXYGEN SUPPLEMENTATION
Oxygen supplementation is not recommended as a primary treatment for OSA. (Option)
NASAL CORTICOSTEROIDS
Topical nasal corticosteroids may improve the AHI in patients with OSA and concurrent rhinitis and, thus, may be a useful
adjunct to primary therapies for OSA. (Guideline)
MODAFINIL, ARMODAFINIL
Modafinil is recommended for treatment of residual excessive sleepiness in OSA patients who have sleepiness despite
effective PAP treatment and who are lacking any other identifiable cause for their sleepiness. (Standard)
OTHER TREATMENTS (NOT RECOMMENDED)
Protriptyline, SSRIs, aminophylline, estrogen preparations with or without progesterone, and short-acting decongestants.
AHI = apnea-hypopnea index; OSA = obstructive sleep apnea; PAP = positive airway pressure; SSRIs = selective serotonin reuptake inhibitors.

outcome assessments that were suggested in recent clinical 100

guidelines.1 A follow-up sleep study is recommended after
upper airway surgery for moderate to severe OSA1,4,5,27 and
after final adjustment of an OA as treatment for all severities
of OSA.5 30
Sleep apnea index

MEDICAL TREATMENTS FOR OSA

10
Practice parameters have been published for use of medical
treatments for OSA3 including weight loss, positioning,
medications, oxygen, and alerting agents (Table 186). Doc-
umentation of the effectiveness of treatment and continued 3
monitoring of adherence are important.

Weight Loss
Obesity is a major risk factor for the development of OSA.
In some studies, approximately 70% of patients with OSA
were obese (body weight > 120% of predicted). In the Wis-
consin cohort study, for every standard deviation increase in
the body mass index (BMI), there was a fourfold increase in
the prevalence of OSA.28 A BMI of 25.0 to 29.9 kg/m2 is
considered overweight, greater than 30 is obesity, and greater
than 40 is severe obesity. Many studies have documented
that weight loss of modest proportions (510%) can produce
significant improvement in sleep apnea2934 as well as decrease
upper airway collapsibility.35
80 90 100 110 120
Body weight (kg)
FIGURE 181 Decrease in apnea-hypopnea index (AHI) with weight loss. The y axis is
a logarithmic scale. The weight loss was due to medication. From Browman CP, Sampson
MG, Yolles SF, et al: Obstructive sleep apnea and body weight. Chest 1984;85:435436.
Figure 181 illustrates the AHI versus weight of a patient
undergoing weight loss.29 Even patients with mild obesity
(110115% of ideal body weight) can benefit from weight
reduction.30 Peppard and colleagues34 followed the effects of
weight change on AHI. A 10% weight gain predicted an
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304 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments

approximate 32% increase in the AHI. A 10% weight loss TABLE 187
predicted a 26% reduction in the AHI. A 10% increase in Selected Studies of Weight Loss in Obstructive
weight was associated with a sixfold increase in the risk of Sleep Apnea
developing moderate to severe OSA. WEIGHT REDUCTION AT 1 YR IN MILD OSA WITH VERY
The effectiveness in reducing the AHI with weight loss LOW CALORIE DIET*
varies among patients. This may be due to the fact that a
given amount of weight loss may have more effect on upper CONTROL INTERVENTION
body obesity or upper airway anatomy in one individual Weight (kg) 92.3 101.2
than in another. One study found that neck fat was the best
AHI (#/hr) 9.3 10.0
predictor of a high AHI in women whereas central obesity
was a better predictor in men.36 Weight loss may also be less AHI supine 21.3 20.1
effective in reducing the AHI if skeletal abnormalities play a Change in AHI 0.3 4.0
more prominent role in the pathogenesis of OSA in a given
Change in weight (kg) 2.4 10.7
patient. The level of nasal CPAP required to maintain upper
airway patency may decrease after weight reduction. Lettieri EFFECTS OF A VERY LOW ENERGY DIET (9 WK)

and associates37 reported a reduction in required CPAP from CONTROL INTERVENTION

11.5 to 8.4 cm H2O after weight loss (BMI dropped from 51
Weight (kg)Baseline 111.7 113.4
to 32 kg/m2) in a group of patients undergoing bariatric
surgery. However, the magnitude of this effect can vary sig- Change in weight (kg) 1.1 18.7
nificantly between patients. AHI (#/hr)Baseline 37 37
Behavioral, surgical, and pharmacologic approaches to
weight loss have all been successful in selected groups of Change in AHI 2 25
patients. The major problem to date has been maintenance EFFECTS OF MILD TO MODERATE WEIGHT LOSS

of weight loss. Johansson and coworkers31 (Table 187)
studied the effects of a very low energy diet on OSA in
patients on CPAP (intervention vs. control group) with
moderate to severe OSA. At 9 weeks, the intervention group
had lost weight (18.8 kg) with a drop in AHI of 23/hr.
Tuomilehtol and colleagues32 reported on use of lifestyle
intervention and weight reduction in mild OSA. Although
both the weight and the AHI decreases were small, a signifi-
cant number of the intervention group dropped their AHI
below 5/hr. In the AHEAD (Action for Health in Diabetes)
study, weight loss also resulted in a drop in the AHI.33
Grunstein and associates38 reported on a 2-year reduction in
sleep apnea symptoms following surgically induced weight
loss. Another study of the effect of the weight reduction with
subitramine found a reduction of 7.9 kg was associated with
a 30% reduction in the AHI (change in AHI 16/hr).39
Today, bariatric surgery is performed as a treatment for
morbid obesity.40,41 However, it could be considered as an
adjunctive treatment for OSA. The most common bariatric
operation is a Roux-en-Y procedure, although other surgery
such as laparoscopic gastric banding may be tried for less
obese patients. The mortality of the Roux-en-Y procedure is
less than 2%.40,41 Greenburg and coworkers42 performed a
meta-analysis of bariatric surgery and the effects on OSA in
morbidly obese patients. Twelve studies including 342
patients were analyzed. The mean BMI was reduced by
17.9 kg/m2 (baseline 55.3 kg/m2) and the AHI was reduced
from 54.7 to 15.8/hr. The authors concluded that bariatric
surgery does result in both dramatic weight loss and improve-
ment of the AHI, but not always to normal levels. Many
patients will still likely require treatment of OSA (CPAP and
others). In another series of 24 consecutive patients under-
going bariatric surgery, only 4% were cured of OSA.40 Pillar
and colleagues43 reported on a patient who had recurrence
BASELINE WEIGHT LOSS
Weight (kg) 106 96.9
Apnea index 55 29.2
AHI = apnea-hypopnea index; OSA = obstructive sleep apnea.
*Adapted from Tuomilehto HPI, Seppa JM, Partine MM, et al: Lifestyle
intervention with weight reduction: first-line treatment in mild obstructive
sleep apnea. Am J Respir Crit Care Med 2009;179:320327.
From Johansson K, Neovius M, Lagerros YT, et al. Effect of a very low energy
diet on moderate and severe sleep apnea in obese men: a randomised
controlled trial. BMJ 2009;339:b4609.
From Smith PL, Gold AR, Meyers DA, et al: Weight loss in mildly to
moderately obese patients with obstructive sleep apnea. Ann Intern Med
1985;103:850855.
of OSA after previous weight loss without concomitant
weight gain. This illustrates the need for continued clinical
follow-up. Sampol and associates44 followed 24 patients
cured by weight loss for a mean of 94 months. Six of the
13 patients who maintained weight loss had recurrence of
OSA (AHI = 40.5/hr).
The AASM practice parameters for use of medical treat-
ments for OSA recommended that weight loss be combined
with a primary treatment for OSA3 (see Table 186). This
recommendation is based on the fact that weight loss takes
time, results vary between patients, and OSA can recur even
if initially improved by weight loss. It was stated that bariat-
ric surgery may be adjunctive in treatment of OSA in obese
patients. This recommendation falls short of recommenda-
tion of bariatric surgery as a primary treatment for OSA
treatment given the variable improvement in the AHI.
Patients with OSA undergoing bariatric surgery should be
treated with an effective treatment (usually CPAP) in the
postoperative period and during weight loss. If a sleep study
after significant weight loss documents a cure, stopping
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primary treatment could be considered. If significant OSA is
still present, a lower level of CPAP may be effective.37 If
CPAP or other treatment for OSA is stopped, patients should
be followed closely for signs and symptoms of recurrence
(Table 188).
Posture and Positional Treatment
Many patients with OSA have a significant worsening of
apnea in the supine position.45 Some but not all studies have
found an increase in upper airway size in the lateral position.
Walsh and coworkers,46 using optical coherence tomography
in awake normal subjects and patients with sleep apnea,
found airway size not to change (supine to lateral) but airway
shape was more circular (Fig. 182A). A circular shape may
be more resistant to closure. In contrast, Isono and col-
leagues47 found a larger airway in the lateral position in
anesthetized normal subjects. Walsh and coworkers46 did not
find a difference in shape between OSA patients and normal
TABLE 188
Weight Loss Treatment for Obstructive
Sleep Apnea
Weight loss is considered a secondary or adjunctive
treatment.
Modest weight loss can be helpful (10% weight loss is
associated with a 26% reduction in the AHI).
Recurrence of OSA can occur after previous weight loss
despite maintenance of lower weight.
Bariatric surgery rarely cures patients of OSA but may
reduce the required level of CPAP.
AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure;
OSA = obstructive sleep apnea.
individuals. However, other studies have found OSA patients
to have an upper airway with narrower lateral dimensions
(see Fig. 182B).48,49 Changes in airway shape or size with
changes in posture could be due to an effect of gravity on the
tissue surrounding the upper airway or to posterior move-
ment of the tongue. Reductions in lung volume in the supine
position may also reduce upper airway size. A limitation of
many studies of the upper airway in OSA patients is that the
patients were evaluated either awake or under anesthesia.
Neither of these circumstances may accurately represent
what happens during sleep.
Neill and associates50 found that elevation of the head by
30 improved airway stability (compared with the supine
position) in OSA patients as measured by airway occlusion
during sleep. In this study, lateral sleep positioning had less
of a stabilizing effect compared with elevation of the head.
This suggests that sleeping with the head elevated may reduce
the AHI more in some patients than sleeping in the lateral
position. In the same study, CPAP was also progressively
elevated until apneas and hypopneas were abolished. The
mean effective pressure was 10.4 cm H2O in the supine posi-
tion, 5.3 cm H2O with the head-elevated position, and 5.5 cm
H2O in the lateral position.
A considerable number of patients with a significant
overall AHI will have minimal sleep apnea in the lateral
position. In fact, many of these patients have chronically
favored this position at home. In one study, approximately
55% of a large group of patients with sleep apnea had posi-
tional sleep apnea, defined as an AHI at least two times
higher in the supine than in the nonsupine position.45
Because the amount of supine sleep can dramatically affect
the overall AHI, one must always note the amount of
supine sleep when interpreting a sleep study or comparing
the results of different sleep studies.
Avoiding the supine posture has been proposed as a treat-
ment for sleep apnea. To maintain the lateral posture during

SUPINE LATERAL RECUMBENT

A L A A

A PA P L R L R
L PA L
P P
P L

BE BE Normal OSA

Gravity
A B
FIGURE 182 A, Schematic of changes in upper airway shape. In the lateral position the pharyngeal airway (PA) has a rounder
shape. A = anterior; BE = bony enclosure; L = lateral; P = posterior. B, Schematic of upper airway shape found in normal and
obstructive sleep apnea (OSA) patients with the supine position in other studies. R = right. A, From Walsh JH, Leigh MS, Paduch A,
et al: Effect of body posture on pharyngeal shape and size in adults with and without obstructive sleep apnea. Sleep 2008;31:15431549.
B, From Schwab RJ, Gefter WB, Hoffman EA, Pack AI: Dynamic upper airway imaging during awake respiration in normal subjects and
patients with sleep disordered breathing. Am Rev Respir Dis 1993;148:1385.
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306 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments
A B
FIGURE 183 A, and B, A lateral positioning device. The ZZsoma Positional Sleeper. From Permut I, Diaz-Abad M, Eissam C, et al: Comparison of positional
therapy to CPAP in patients with positional obstructive sleep apnea. J Clin Sleep Med 2010;6:238243.
sleep, a number of night shirts or straps with foam balls or
cushions are available that prevent comfortable supine
sleep51,52 (Fig. 183). Another approach was training with
an auditory alarm when patients turn supine.53 Jokic and
coworkers52 performed a randomized cross-over trial of
position therapy and CPAP in a group of patients with posi-
tional OSA. The positional device consisted of a backpack
with a foam ball (10 5.5 inches). Positional treatment was
slightly less effective than CPAP but there was no difference
in improvement in the ESS, sleep architecture, or subjective
sleep quality. There have been no long-term studies of posi-
tional therapy. Permut and colleagues51 found positional
treatment (see Fig. 183) to be as effective as CPAP as
assessed by one night of PSG in a group of patients with mild
and positional OSA. McEvoy and associates54 also found a
lower AHI, better oxygen saturation, and better sleep quality
in the seated sleeping posture (60) compared with the
supine position. Skinner and coworkers55 studied the effect
of a shoulder-head elevation pillow in mild to moderate
OSA. In 7 of 14 patients, the AHI dropped to less than 10/
hr. In contrast with CPAP, the AHI was less than 5/hr in all
patients. There seems little doubt that positional treatment
would work in a number of patients with positional OSA.
However, a recent study found poor adherence to the tennis
ball technique.56 Studies of long-term outcomes with more
comfortable positioner devices are needed.
An increase in the required CPAP pressure to maintain
upper airway patency is commonly required in the supine
compared with the lateral body position.57,58 Oksenberg and
colleagues57 documented about a 3-cm H2O difference
between supine and nonsupine postures. As noted previ-
ously, Neill and associates50 noted a significantly lower PAP
was needed in the lateral position or with the head elevated.
In pressure-intolerant patients undergoing CPAP treatment,
one approach might be to lower the pressure to one effective
in the lateral position and encourage patients to sleep in that
position (or use a device to discourage supine sleep), at least
during an adaptation period. Nocturnal oximetry at home
and/or observation of the residual AHI recorded on the
TABLE 189
Treatment of Nasal Congestion/Rhinitis3
Short-acting nasal decongestants are not recommended
for treatment of OSA. (Option)
Topical nasal corticosteroids may improve the AHI in
patients with OSA and concurrent rhinitis and, thus, be
useful adjuncts to primary therapies for OSA. (Guideline)
AHI = apnea-hypopnea index; OSA = obstructive sleep apnea.
CPAP device are methods to document the efficacy of this
approach.
Medical Therapies to Improve Nasal Patency
The AASM practice parameters for medical treatment3 did
not recommend use of short-acting nasal decongestants
(Table 189). The major consideration is the development of
rhinitis medicamentosa.59 A study by Kiely and associates,60
using a placebo-controlled, randomized, cross-over design,
found a modest reduction in the AHI in a group of apneic
snorers with intranasal fluticasone but no reduction in
snoring noise in nonapneic snorers. There was no improve-
ment in objective sleep quality. Of interest, the improvement
in the AHI was correlated with a reduction in the nasal
resistance. A treatment effect is likely only if intranasal ste-
roids improve nasal resistance, and this change may not
occur in all patients.
Supplemental Oxygen
Supplemental oxygen can improve nocturnal oxygenation in
patients with OSA. In a study by Smith and coworkers,61
nocturnal supplemental oxygen did not improve objective
daytime sleepiness but did improve nocturnal oxygenation
in a group of patients with OSA. In general, oxygen does not
significantly reduce the AHI or improve daytime
sleepiness.6163 Caution is advised in hypercapnic OSA
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 Chapter 18
OXYGEN SATURATION DURING REPETITIVE
OBSTRUCTIVE APNEAS
REM sleep
100
80
60
O2 saturation
REM sleep
100
80
60
0
0 4 8 12 16 20 24 28 32 36
Time in minutes
patients, because some may develop worsening hypercapnia,
especially on high flow rates of oxygen.65 In some studies,
acute administration of oxygen caused prolongation of
apneas.6265 Supplemental oxygen tends to convert central
and mixed apneas to obstructive apneas.66 Loredo and col-
leagues67 compared oxygen with CPAP treatment in OSA.
CPAP improved sleep quality but supplemental oxygen
improved only nocturnal oxygenation. It should also be
noted that supplemental oxygen often improves but does not
normalize nocturnal oxygen saturation in patients with
severe drops in the arterial oxygen saturation65 (Fig. 184).
Norman and associates68 compared supplemental oxygen
with CPAP with respect to changes in blood pressure in a
group of patients with OSA. CPAP reduced daytime and
nighttime blood pressure whereas supplemental oxygen had
no effect. Supplemental oxygen did improve nocturnal oxy-
genation. In summary, supplemental nocturnal oxygen is not
the treatment of choice for OSA, but individual patients may
benefit from this treatment if all other treatment options fail.
The AASM practice parameters for medical treatment of
OSA state that supplemental oxygen is not indicated for
treatment of OSA.3
Persistent Daytime Sleepiness on CPAP
A substantial number of patients with OSA continue to have
daytime sleepiness despite adequate PAP treatment.69,70 In
such patients, the first steps are to document adequate objec-
tive PAP adherence, document effective treatment, and to try
sleep extension if indicated. Other causes of persistent
daytime sleepiness despite PAP treatment include medica-
tions and other sleep disorders (narcolepsy, periodic limb
Obstructive Sleep Apnea Treatment Overview and Medical Treatments 307
FIGURE 184 Effects of supplemental oxygen on oxygen
desaturation during repetitive obstructive apneas. Supplemental
oxygen at 4 L/min did not completely eliminate events (which
NREM sleep
appear slightly longer during rapid eye movement [REM] sleep).
NREM = nonrapid eye movement. From Alford NJ, Fletcher EC,
Nickeson D: Acute oxygen in patients with sleep apnea and COPD. Chest
1986;89:3038.
Room air
NREM sleep
Nasal O2 at 4 L/min
40 44 48 52 56 60
movement disorder, idiopathic hypersomnia, depression).
Other sleep disorders should be ruled out if clinically indi-
cated. Of note, although some might assume 6 to 7 hours of
nightly CPAP adherence to be good adherence, in patients
with continued daytime sleepiness, the first step would be an
attempt at sleep extension. This includes using CPAP during
naps. Another option would be an empirically small increase
in CPAP pressure. Adequacy of pressure should also be doc-
umented because a surprisingly high percentage of patients
remain inadequately treated.71 Many PAP devices today give
an estimate of the residual AHI. Finally, one might consider
a repeat PAP titration if there is any suspicion that the
current level of CPAP is not effective.
Modafinil, Armodafinil, and Stimulants
If daytime sleepiness persists on optimized CPAP treatment
and there is no identifiable additional sleep disorder/cause
of sleepiness, treatment with an alerting agent (modafinil
[Provigil] or armodafinil [Nuvigil]) is indicated.3 These med-
ications have been shown to improve daytime alertness (sub-
jective and objective) using randomized, placebo-controlled
studies in OSA patients with residual sleepiness despite ade-
quate PAP treatment.69,70,7276 Figure 185 illustrates improve-
ment in the ESS in patients taking modafinil compared with
placebo. Figure 186 displays results documenting an
improvement in objective daytime sleepiness (longer sleep
latency) with modafinil compared with placebo. The side
effects of modafinil and use of this medication are discussed
in more detail in Chapter 24. Headache is the most common
side effect of modafinil. The Stevens-Johnson syndrome is a
very rare but severe complication of modafinil treatment.
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308 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments

16 (e.g., upper respiratory tract infection). A recent study by

14.4 14.2
13.2 Williams and coworkers77 documented that use of modafinil
* 12.4 did help the ability of the patients to function in this
Mean ESS score (SEM)

12
10.1
* circumstance.
9.6 Armodafinil (Nu-vigil) is the R enantiomer of modafinil
and has a longer half-life than the L enantiomer. The dose of
8 armodafinil is 150 to 250 mg daily. One would expect
armodafinil to be as effective for daytime sleepiness as
modafinil, but fewer studies have been published.78,79
4 Armodafinil has also been shown to be effective in treatment
of wakefulness in CPAP-adherent patients with OSA with
co-morbid depression.78 This is an important issue because
0 a significant proportion of patients with OSA do suffer from
N  80 77 49 53 80 75 depression.
Baseline Week 1 Week 4 Unfortunately, the addition of modafinil has minimal or
CPAP  Placebo CPAP  Modafinil modest benefits in a significant number of OSA patients who
are still sleepy on PAP treatment. Kingshott and colleagues70
FIGURE 185 Modafinil decreased the Epworth Sleepiness Scale (ESS) compared with
found no improvement in ESS or multiple sleep latency test
placebo at week 1 and week 4. *P = .001 placebo versus modafinil. Modafinil decreased
the ESS compared with placebo. CPAP = continuous positive airway pressure; SEM =
(MSLT) with modafinil but did find an improvement in the
standard error of the mean. From Pack AI, Black JE, Schwartz JR, Matheson JK: Modafinil MWT sleep latency. Although stimulants are not U.S. Food
as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care and Drug Administration (FDA) or AASM practice param-
Med 2001;164:16751681. eter approved for treatment of persistent sleepiness, there are
individual OSA patients with persistent daytime sleepiness
despite adequate PAP treatment who will respond better
10 * to stimulants (methylphenidate, amphetamine) than to
8.6 modafinil. Treatment with stimulants in addition to PAP
Mean sleep latency (SEM) (min)

7.5 7.4 7.2
8
6 situation is discussed in Chapter 24). Performing an over-
4
2 possible (current treatment with an antidepressant), one
0 as a last resort (an off-label treatment).
Baseline Week 4
CPAP  Placebo CPAP  Modafinil
FIGURE 186 Mean multiple sleep latency test (MSLT) sleep latency at baseline and
after treatment with nasal continuous positive airway pressure (nCPAP) and modafinil
or nCPAP plus placebo. *P = .021. Modafinil increased the sleep latency. SEM = standard
error of the mean. From Pack AI, Black JE, Schwartz JR, Matheson JK: Modafinil as adjunct
therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med
2001;164:16751681.
During treatment of OSA patients with modafinil, it is essen-
tial to document continued adequate adherence to PAP
treatment. In one study evaluating the addition of modafinil
to CPAP treatment, poorer CPAP use was noted with
modafinil than with placebo.70 The usual modafinil dose is
200 to 400 mg in the morning. Some patients will benefit
from a split dose if they have an increase in sleepiness in the
late afternoon (modafinil 200 mg q AM and 100200 mg q 2
PM). Patients with OSA who are adherent to PAP treatment
will sometimes not be able to use CPAP for various reasons
could be tried if patients continue to have disabling sleepi-
ness despite other measures. If clinically indicated, the pos-
sibility of coexistent narcolepsy should be ruled out. (This
night sleep study on CPAP followed by an MSLT on CPAP
can help document coexistent narcolepsy. If the MSLT is
positive for narcolepsy, stimulants could certainly be used if
modafinil was not effective. If the MSLT is negative or not
could still try the addition of a stimulant to PAP treatment
Overview of Treatment of Pediatric OSA
Pediatric OSA is diagnosed if the apnea index >1/hr or the
obstructive AHI (OAHI) >12/hr. OAHI values of 1 to <5,
510, and >10/hr are considered to characterize mild, mod-
erate, and severe pediatric OSA.80 These classifications are
arbitrary and fail to account for different susceptibility in
children to sleep disruption or hypoxemia. Patients with an
OAHI <5/hr are treated based on the presence of significant
symptoms. The treatment of choice for most patients with
pediatric OSA is tonsillectomy and adenoidectomy (TNA)
(see Chapter 21). Even if patients are obese or the AHI is
elevated to the severe range, TNA is usually recommended
unless minimal tonsillar and adenoidal tissues are present.
PSG after surgical healing is recommended in all patients by
some clinicians. Certainly, patients with residual symptoms
on a pre-treatment OAHI in the moderate to severe range
should be studied. If a significant residual OAHI is present
after TNA, possible treatments include weight loss, positive
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 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments
airway pressure (see Chapter 20), dental procedures such as
rapid maxillary expansion (see Chapter 21), or medications
to reduce adenoidal and tonsillar inflammation.
Medications for Pediatric OSA
Leukotrienes and their receptors are increased in adenoton-
sillar tissue and exhaled condensates of children with
OSA.81,82 The combination of nasal inhaled steroid and the
leukotriene inhibitors (montelukast) was found to have
benefit in a study of patients with residual sleepiness after
tonsillectomy and adenoidectomy.83
CLINICAL REVIEW QUESTIONS
1. A 40-year-old man without daytime sleepiness undergoes
a PSG. The AHI = 50/hr with a low arterial oxygen satura-
tion (SaO2) of 80%. On physical examination, a very long
uvula and a mild tonsillar enlargement is present. Which
treatment do you recommend?
A. UPPP.
B. CPAP.
C. OA.
D. MMA.
2. A 50-year-old woman with a BMI of 35, AHI of 40/hr
cannot tolerate CPAP. She does not want surgery. What
do you recommend?
A. Bariatric surgery.
B. Nocturnal oxygen.
C. Structured medical weight loss (diet modification).
D. Protriptyline.
E. OA.
3. A 35-year-old woman with previously documented OSA
stopped CPAP of 10 cm H2O after weight loss of 50 pounds
following bariatric surgery was documented to reduce the
AHI to less than 5/hr (study performed without CPAP).
Over the last 6 months, daytime sleepiness has returned,
although snoring is described only as mild. The patients
body weight has not changed since the last sleep study.
What do you recommend?
A. PSG.
B. Thyroid function studies.
C. Modafinil.
D. CPAP of 10 cm H2O
4. A 40-year-old man has persistent severe daytime sleepi-
ness (ESS 15/24) despite good adherence to CPAP of
10 cm H2O (average nightly use of 6 hr). A recent sleep
study showed an AHI of 2/hr on CPAP of 10 cm H2O
during supine REM sleep. The patients wife reports no
snoring or apnea on treatment. He is taking fluoxetine for
depression and denies symptoms of cataplexy. What do
you recommend?
309
A. Sleep extension and, if not successful, modafinil.
B. PSG on CPAP followed by MSLT.
C. Addition of methylphenidate.
D. A repeat PAP PSG titration.
5. A 30-year-old man with a BMI of 19 denies sleepiness but
is a very loud snorer. This is worse when he drinks alcohol
or has worsening of nasal congestion. A sleep study
revealed an overall AHI of 15/hr. He has declined CPAP
or uvuloplasty and cannot afford an OA. An overnight
summary of the sleep study is shown in Figure 187.
What treatment do you recommend?
A. Pillar procedure (palatal implants).
B. Supplemental oxygen.
C. Nasal corticosteroid and positional therapy.
D. Mirtazapine.
Answers
1. B. The treatment of choice for severe OSA is CPAP (or
other PAP treatment) even if some potentially surgically
correctable anatomic changes are present.
2. E. Protriptyline and supplemental oxygen are not recom-
mended treatments for OSA. Weight loss with either a
dietary or a surgical intervention takes time and is con-
sidered a secondary treatment. Although an OA is not the
treatment of choice for severe OSA, it can be effective in
a significant proportion of patients. If severe arterial
oxygen desaturation is present and no other treatments
are acceptable, one might use supplemental oxygen,
although the benefit of oxygen treatment for OSA is
unproven. A sleep study on OA treatment should be per-
formed to document efficacy.
3. A. A PSG is indicated to determine whether significant
OSA has returned. This can occur after bariatric surgery
even if weight loss has been maintained. Restarting CPAP
is not indicated without documentation of the need for
treatment and lower pressure may be effective. If a PSG
documents significant OSA, a PSG PAP titration can be
performed to determine an effective pressure level at the
new lower weight.
4. A. Of the answers presented, this is the best option. An
MSLT is often of limited value if a patient is taking a
selective serotonin reuptake inhibitor. Methylphenidate is
not FDA approved for treatment of residual daytime
sleepiness on CPAP treatment. A repeat PSG CPAP titra-
tion is not unreasonable, but a recent study showed good
control at the current treatment pressure.
5. C. The figure reveals postural OSA with few respiratory
events in nonsupine positions. Nasal corticosteroids and
positional therapy are the best answer, although the long-
term effectiveness of positional therapy is unproved.
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310 Chapter 18 Obstructive Sleep Apnea Treatment Overview and Medical Treatments
Wake
REM
Stage 1
2
3
95%
SpO2
90%
85%
Respiratory
event
Left
Right
Position Prone
Supine
FIGURE 187 Overnight summary of the sleep study. REM = rapid eye movement; SpO2 = pulse oximetry.
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obstructive sleep apnea. Am J Respir Crit Care Med 1997;155:
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51. Permut I, Diaz-Abad M, Eissam C, et al: Comparison of posi-
tional therapy to CPAP in patients with positional obstructive
sleep apnea. J Clin Sleep Med 2010;6:238243.
52. Jokic R, Klimaszewski A, Crossley M, et al: Positional treatment
vs continuous positive airway pressure in patients with posi-
tional obstructive sleep apnea syndrome. Chest 1999;115:
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53. Cartwright RD, Lloyd S, Lilie J, Kravitz H: Sleep position train-
ing for sleep apnea syndrome: a preliminary study. Sleep 1985;
8:8794.
54. McEvoy RD, Sharp DJ, Thornton AT: The effects of posture
on obstructive sleep apnea. Am Rev Respir Dis 1986;133:
662666.
55. Skinner MA, Kingshott RN, Jones DR, et al: Elevated posture
for the management of obstructive sleep apnea. Sleep Breath
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56. Bignold JJ, Deans-Costi G, Goldsworthy MR, et al: Poor long-
term patient compliance with the tennis ball technique for
treating positional obstructive sleep apnea. J Clin Sleep Med
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57. Oksenberg A, Silverberg DS, Arons E, et al: The sleep supine
position has a major effect on optimal nasal CPAP. Chest 1999;
116:10001006.
58. Pevernagie DA, Shepard JW Jr: Relations between sleep stage,
posture and effective nasal CPAP levels in OSA. Sleep 1992;
15:162167.
59. Doshi J: Rhinitis medicamentosa: what an otolaryngologist
needs to know. Eur Arch Otolaryngol 2009;266:623625.
60. Kiely JL, Nolan P, McNicholas WT: Intranasal corticosteroid
therapy for obstructive sleep apnea in patients with co-existing
rhinitis. Thorax 2004;59:3555.
61. Smith PL, Haponik EF, Bleecker ER: The effects of oxygen
in patients with sleep apnea. Am Rev Respir Dis 1984;130:
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62. Martin RJ, Sander MH, Gray BA, Pennock BE: Acute and long
term ventilatory effects in adult sleep apnea. Am Rev Respir
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63. Gold AR, Schwartz AR, Bleecker ER, Smith PL: The effect of
chronic nocturnal oxygen administration upon sleep apnea.
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64. Fletcher E, Munafo DA: Role of nocturnal oxygen therapy
in obstructive sleep apnea. Should it be used? Chest 1990;
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65. Alford NJ, Fletcher EC, Nickeson D: Acute oxygen in patients
with sleep apnea and COPD. Chest 1986;89:3038.
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66. Gold AR, Bleecker ER, Smith PL: A shift from central and
mixed sleep apnea to obstructive sleep apnea resulting from
low flow oxygen. Am Rev Respir Dis 1985;132:220223.
67. Loredo JS, Ancoli-Israel S, Kim E, et al: Effect of continuous
positive airway pressure versus supplemental oxygen on sleep
quality in obstructive sleep apnea: a placebo-CPAP-controlled
study. Sleep 2006;29:564571.
68. Norman D, Loredo JS, Nelesen RA, et al: Effects of continuous
positive airway pressure versus supplemental oxygen on 24
hour ambulatory blood pressure. Hypertension 2006;47:
840845.
69. Pack AI, Black JE, Schwartz JR, Matheson JK: Modafinil as
adjunct therapy for daytime sleepiness in obstructive sleep
apnea. Am J Respir Crit Care Med 2001;164:16751681.
70. Kingshott RN, Vennelle M, Coleman EL, et al: Randomized,
double-blind, placebo-controlled crossover trial of modafinil in
the treatment of residual excessive daytime sleepiness in the
sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med
2001;163:918923.
71. Pittman SD, Pillar G, Berry RB, et al: Follow-up assessment of
CPAP efficacy in patients with obstructive sleep apnea using an
ambulatory device based on peripheral arterial tonometry.
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72. Dinges DF, Weaver TE: Effects of modafinil on sustained atten-
tion performance and quality of life in OSA patients with
residual sleepiness while being treated with nCPAP. Sleep Med
2003;4:393402.
73. Schwartz JR, Hirshkowitz M, Erman MK, Schmidt-Nowara W:
Modafinil as adjunct therapy for daytime sleepiness in obstruc-
tive sleep apnea: a 12-week, open-label study. Chest 2003;124:
21922199.
74. Black JE, Hirshkowitz M: Modafinil for treatment of residual
excessive sleepiness in nasal continuous positive airway
pressuretreated obstructive sleep apnea/hypopnea syndrome.
Sleep 2005;28:464471.
75. Weaver TE, Chasens ER, Arora S: Modafinil improves
functional outcomes in patients with residual excessive sleepi-
ness associated with CPAP treatment. J Clin Sleep Med 2009;
5:499505.
76. Roth T, Rippon GA, Arora S: Armodafinil improves wakeful-
ness and long-term episodic memory in nCPAP-adherent
patients with excessive sleepiness associated with obstructive
sleep apnea. Sleep Breath 2008;12:5362.
77. Williams SC, Marshall NS, Kennerson M, et al: Modafinil
effects during acute continuous positive airway pressure
withdrawal: a randomized crossover double-blind placebo-
controlled trial. Am J Respir Crit Care Med 2010;181:
825831.
78. Krystal AD, Harsh JR, Yang RR, et al: A double-blind, placebo-
controlled study of armodafinil for excessive sleepiness in
patients with treated obstructive sleep apnea and comorbid
depression. J Clin Psychiatry 2010;71:3240.
79. Roth T, Schwartz JR, Hirshkowitz M, et al: Evaluation of the
safety of modafinil for treatment of excessive sleepiness. J Clin
Sleep Med 2007;3:595602.
80. Katz ES, DAmbrosio CM: Pediatric obstructive sleep apnea
syndrome. Clin Chest Med 2010;31:221234.
81. Goldbart AD, Goldman JL, Li RC, et al: Differential expression
of cysteinyl leukotriene receptors 1 and 2 in tonsils of children
with obstructive sleep apnea syndrome or recurrent infection.
Chest 2004;12:613618.
82. Goldbart AD, Krishna J, Li RC, et al: Inflammatory mediators
in exhaled condensate of children with obstructive sleep apnea
syndrome. Chest 2006;130:143148.
83. Kheirandish L, Goldbart AD, Gozal D: Intranasal steroids and
oral leukotriene modifier therapy in residual sleep-disordered
breathing after tonsillectomy and adenoidectomy in children.
Pediatrics 2006;117:e61e66.
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Positive Airway Pressure
Treatment
Chapter Points
PAP is the treatment of choice for patients with
moderate to severe OSA and is an option in
symptomatic patients with mild OSA.
Although many variants of PAP have been developed,
CPAP remains the treatment of choice for most OSA
patients.
BPAP devices deliver separately adjustable IPAP and
EPAP with IPAP > EPAP.
APAP devices provide the lowest effective pressure for
a given posture and sleep stage.
BPAP, APAP, or flexible PAP devices have not
significantly improved adherence to PAP treatment for
unselected patients. However, individual patients may
benefit from these treatment modes.
BPAP in the spontaneous mode is used for pressure
intolerant OSA patients and to deliver pressure
support (PS = IPAP EPAP).
BPAP in the ST mode (backup rate) is used for NPPV
treatment of patients who have central apneas or
central ventilatory control disorders.
BPAP-ST is also used for patients who may not reliably
trigger a transition for EPAP to IPAP due to
neuromuscular or chest wall disorders.
ASV is used for patients with an instability in
ventilatory control manifested by CSB-central apneas,
central apneas from narcotics, or CompSA of unknown
etiology that does not improve with chronic CPAP
treatment.
PAP treatment is very effective at reversing or
improving many manifestations of OSA. However,
acceptance and adherence are major problems.
There is a dose response to CPAP usage with the
Epworth Sleepiness Scale improving with as little as 4
hours of use but objective improvement in sleepiness
and quality of life measures usually require longer
CPAP use for maximal benefit.
Objective monitoring of adherence is essential for
successful PAP treatment. This should be performed
Chapter 19
early after treatment initiation and at continuous
intervals.
Documentation of adequate objective adherence is
the first step to evaluate persistent sleepiness despite
PAP treatment.
A PSG PAP titration is the standard approach for
choosing an effective pressure.
Higher CPAP is needed in the supine position and
during REM sleep.
Unattended APAP titration can be used to determine
an effective level of CPAP (90th or 95th percentile
pressure).
Chronic treatment with APAP devices in properly
selected patients eliminates the need for a PSG
titration but does not significantly improve
adherence.
Since the original description of continuous positive airway
pressure (CPAP) treatment for obstructive sleep apnea
(OSA) by Sullivan, Issa, and Berthon-Jones in 1983,1 positive
airway pressure (PAP) remains the mainstay of treatment for
moderate to severe OSA in adults.25 Despite many advances
in technology, the major challenge facing clinicians is
improving adherence to PAP treatment.6
MECHANISM OF ACTION
PAP works by splinting the upper airway open during
sleep.79 Studies have shown CPAP to increase upper airway
size, especially in the lateral dimension (Fig. 191). Positive
intraluminal pressure expands the upper airway (pneumatic
splint). This is a passive process because upper airway muscle
activity is reduced by CPAP.10 Although the pneumatic splint
is the main mechanism of action, an increase in lung volume
due to CPAP may also increase upper airway size and/or
stiffen the upper airway walls, making them less collapsible.
In general, upper airway size increases as lung volume
increases.11 This is thought due to a downward pull on upper
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313
314 Chapter 19 Positive Airway Pressure Treatment

FIGURE 191 Change in the upper airway of a

normal individual after application of continuous
positive airway pressure (CPAP) of 0 cm H2O (A) and
CPAP of 15 cm H2O (B). The airway increases in size
mainly in the lateral dimension. From Schwab RJ:
Upper airway imaging. Clin Chest Med 1998;19:3354.

A
B

TABLE 191
Modes of Positive Airway Pressure Devices
CPAP Continuous pressure during inhalation and exhalation.
BPAP (S mode) IPAP.
EPAP.
IPAP EPAP = PS.
BPAP may be better tolerated in patients complaining of difficulty exhaling on CPAP.
Flexible PAP, expiratory pressure Pressure falls in early exhalation.
relief (Cflex, EPR) Returns to set pressure at end-exhalation.
APAP autotitrating, Titrates between maximum and minimum pressure limits to prevent apnea,
autoadjusting PAP (autoCPAP) hypopnea, airflow flattening, and airway vibration (snoring).
Auto-BPAP Titrates IPAP and EPAP between EPAPmin and IPAPmax with PSmin = 3 and PSmax set
by the clinician. PSmax constrained by IPAPmax.
BPAP with backup rate (NPPV) BPAP modes
ST.
T.
ASV PS varies to stabilize breathing.
EPAP set to eliminate airway obstruction.
Backup rate AVAILABLE (see Table 192).
APAP = autoadjusting positive airway pressure; ASV = adaptive servoventilation; BPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure;
EPAP = expiratory positive airway pressure; EPR = expiratory pressure relief; IPAP = inspiratory positive airway pressure; NPPV = noninvasive positive pressure
ventilation; PAP = positive airway pressure; PS = pressure support; S mode = spontaneous mode; ST = spontaneous timed mode; T = timed mode.

airway structures during lung expansion (tracheal tug).12
Whereas CPAP maintains a positive intraluminal pressure
during both inspiration and expiration, one study using only
expiratory positive airway pressure (EPAP) showed a reduc-
tion in respiratory events.13Another study was not able to
reproduce a beneficial effect of EPAP.14 This could be due to
differences in study design or the method of delivery of
EPAP (threshold valve vs. expiratory resistance).
EFFECTIVENESS
Numerous studies have shown that PAP can bring the apnea-
hypopnea index (AHI) down to below 5 to 10/hr in the
majority of patients.2 The virtual elimination of apnea and
hypopnea improves arterial oxygen saturation and decreases
respiratory arousals. In some patients, PAP treatment can
also increase the amount of stage N3 and stage R (rapid eye
movement [REM] sleep). An occasional patient with very
severe apnea will have a large REM or stage N3 sleep rebound
on the first night of PAP treatment. This is most commonly
seen when an entire night of polysomnography (PSG) is
available for PAP titration. The most difficult problem with
PAP treatment is that adherence is suboptimal in a large
percentage of patients.6 Many of the benefits of PAP treat-
ment are discussed in Chapter 17.
MODES OF PAP
A number of modes of delivering PAP exist (Table 191).
CPAP delivers a predetermined constant pressure during
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I Inspiration E Exhalation
Airway pressure (cm H2O)
I E
10
0
CPAP 10 BPAP 15/5
both inspiration and exhalation (Fig. 192). Bilevel positive
airway pressure (BPAP) delivers separately adjustable higher
inspiratory positive airway pressure (IPAP) and lower EPAP
(see Fig. 192).15 Of note, in unselected patients, BPAP treat-
ment does not result in higher rates of adherence than
CPAP.16 A Cochrane database analysis of six studies and 285
participants found no significant difference in usage with
BPAP compared with CPAP.17 However, some patients failing
CPAP will tolerate BPAP.18,19 This is especially true of patients
having difficulty exhaling or with complaints of bloating. The
IPAP-EPAP differential (pressure support [PS]) is useful for
augmenting ventilation in patients with OSA and concomi-
tant hypoventilation. These groups include the obesity
hypoventilation syndrome (OHS) and the overlap syn-
drome (OSA + chronic obstructive pulmonary disease
[COPD]). Some patients with the OHS or the overlap syn-
drome can be adequately treated with CPAP alone.20,21
However, other patients in this group require BPAP, espe-
cially if significant hypoventilation is present.
BPAP is also used for noninvasive positive pressure ven-
tilation (NPPV) in chronic alveolar hypoventilation syn-
dromes.22 In patients with OSA and OHS, BPAP is usually
used in the spontaneous (S) mode. In this mode, the patient
cycles the device from EPAP to IPAP and sets the respiratory
rate. BPAP is also available with a backup rate (spontaneous-
time [ST] mode) or a set respiratory rate (timed [T] mode).
These modes are used to provide NPPV to patients who
unreliably cycle the device between IPAP and EPAP due to
muscle weakness or abnormal central ventilatory control
(central apnea). In the ST mode, the device will provide a
machine-triggered breath with the specified IPAPtime
(inspiratory time) if no spontaneous breath occurs within a
time window. For example, if the backup rate is 12 breaths/
min, there is a 5-second window following the start of
the last breath. If no spontaneous breath occurs during the
time window, the machine will deliver a machine-triggered
breath (Fig. 193). In the T mode, the device delivers IPAP/
EPAP cycles with a set IPAPtime at a specified respiratory
rate. For example, with a rate of 20, the cycle time is 3
seconds. If IPAPtime = 1 sec, then EPAP time = 2 sec. The
Chapter 19 Positive Airway Pressure Treatment 315
FIGURE 192 Modes of positive airway pressure used to treat
obstructive sleep apnea (OSA). BPAP = bilevel positive airway
pressure; CPAP = continuous positive airway pressure.
I I I
E E
CPAP 10 with
expiratory
pressure relief
IPAP time is usually set at 1.2 to 1.6 seconds depending
on the backup rate.
Autoadjusting (autotitrating) positive airway pressure
(autoCPAP, autoPAP, APAP) devices were developed with
two potential uses: (1) autotitrating PAP to select an effective
level of CPAP without the need for an attended titration and
(2) autoadjusting PAP for chronic treatment with the advan-
tage of delivering the lowest effective pressure in any
circumstance.2326 Chronic treatment with APAP would also
eliminate the requirement for a CPAP titration. When APAP
was first developed, improvement in PAP adherence was a
goal. Although there are conflicting data, one meta-analysis
showed that APAP does not improve adherence compared
with CPAP.27 A more recent larger meta-analysis of 30 studies
and 1136 participants found a statistically significant differ-
ence in machine usage of 0.21 hour (12 min), which is not
clinically significant.17 However, individual patients may tol-
erate APAP better than CPAP.
The APAP algorithms vary between different devices, but
in most instances, the pressure changes in response to varia-
tions in airflow magnitude (apnea or hypopnea), airflow
limitation (flattening of the airflow contour), snoring (vibra-
tion), and/or airway impedance.23 The pressure changes
gradually between the preset lower and upper pressure limits
(Pmax, Pmin) to avoid inducing arousal. If none of the mon-
itored variables is detected, the device slowly lowers the pres-
sure to a minimum effective setting. The pressure varies
during the night in response to changes in body position or
sleep stage that may alter the pressure required to maintain
an open upper airway (Fig. 194). The average pressure is
typically only 2 to 3 cm H2O lower than the fixed pressure
that would be effective during the entire night but can be up
to 6 cm H2O lower.28 Of note, different brands of devices may
respond very differently to changes in airflow.29 High air leak
(mask or mouth leak), which simulates physiologic events,
and inability to differentiate between central and obstructive
apnea by these devices can result in errors in APAP titra-
tion.23,30 The APAP devices have no method of determining
whether inspiratory effort is present during an apnea. In the
past, some autotitration algorithms would not titrate above
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316 Chapter 19 Positive Airway Pressure Treatment

A B C D
Flow

5 sec
5 sec
20
Pressure 5

1.8 sec
1.2 sec

Leak

1000 ml
Tidal
volume
0

FIGURE 193 Tracings of flow, pressure, leak, and tidal volume signals provided by the positive airway pressure device while a
patient is breathing on BPAP spontaneous timed (ST) mode with a backup rate of 12 breaths/min. Breaths A and C are patient-
initiated and breaths B and D are machine-cycled breaths. If the device does not cycle from expiratory positive airway pressure
(EPAP) to inspiratory positive airway pressure (IPAP) within a 5-second window, a machine breath (IPAPcycle) for the chosen
inspiratory time (IPAPtime) occurs (breath B). The particular noninvasive positive airway pressure (NPPV) device illustrated supplies
a negative-pressure spike signifying a machine-triggered breath. Note the shorter inspiratory time in breath B compared with
breath A. Although the peak flow rates are similar, the tidal volume differs between breaths A and B due to a different IPAPtime.
This illustrates the utility of recording tidal volume as well as flow.

PRESSURE 10 cm H2O unless snoring or airflow limitation was present.

20
Other algorithms would not continue to increase pressure if
15 this did not reduce apnea (nonresponsive apnea). New tech-
cm H2O

10 nology used by Philips-Respironics attempts to differentiate

clear airway apneas versus obstructive apneas by delivering
5
a small pressure pulse (12 cm H2O pressure pulse) after
0 approximately 6 seconds of a reduction in airflow (Fig. 19
0 1 2 3 4 5 6 7
5). If the pressure pulse does produce an increase in flow,
Time (hrs)
this is compatible with an open airway (clear airway). If the
FIGURE 194 A single-night tracing of a patient using autoadjusting positive airway pressure pulse does not increase flow, the airway is closed.
pressure (APAP) to determine an effective level of CPAP. The pressure limits were Pmax An APAP device using this technology does not increase
= 18 and Pmin = 4. The 95th percentile pressure was 9.8 cm H2O. A CPAP of 10 cm H2O pressure for clear airway apneas. Note that a closed airway
was chosen for chronic treatment.

FIGURE 195 Method of determining whether an apnea is associated

with an open airway (clear airway apnea) or a closed airway (obstructive
apnea). The method cannot tell whether there is inspiratory effort, so Clear
a closed airway central apnea is labeled as an obstructive apnea. CPAP Flow airway
= continuous positive airway pressure. apnea

CPAP

Obstructive
Flow
apnea

CPAP

80-90% reduction in flow for 6 seconds results in a

short pulse of pressure. Here, obstructive apnea
really means closed airway apnea because
inspiratory effort is not monitored.

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 Chapter 19 Positive Airway Pressure Treatment 317

can occur with some central apneas.31 Thus, using this
approach, some apneas classified as obstructive could
actually be closed airway central apneas. The use of APAP
devices for autotitration is discussed in more detail in later
sections.
An autoBPAP device is also available (Fig. 196). The
physician sets the minimum EPAP, and the minimum and
maximum pressure support (IPAP-EPAP), as well as the
maximum IPAP. The minimum PS is 3 cm H2O by default.
The machine then adjusts both the EPAP and the IPAP to
maintain an open airway. The advantages of autoBPAP over
other PAP modes remain to be demonstrated. A recent study
found autoBPAP to be useful as rescue therapy in patients
not compliant to CPAP treatment in spite of the usual inter-
ventions.32 Thus, autoBPAP could potentially be useful in
very pressure-intolerant patients who find BPAP alone unac-
ceptable or in patients for whom an effective bilevel pressure
is not known.
Adaptive servoventilation (ASV)3338 is a variant of BPAP
that was developed to treat Cheyne-Stokes central apnea in
patients with congestive heart failure.33,37,38 Both ASV and
BPAP devices with a backup rate are approved for use with
patients with central apnea and complex sleep apnea
(CompSA; central apnea that persists or appears during a
PAP titration). ASV devices attempt to stabilize ventilation
in patients with ventilatory instability such as Cheyne-Stokes
breathing (CSB),33,37,38 narcotic-induced central apnea,36 and
CompSA of unknown etiology.34,35 During an ASV titration,
a level of EPAP is chosen to keep the upper airway open
(preventing obstructive apnea) and the IPAP-EPAP differ-
ence (PS) automatically adapts between minimum and
maximum levels to stabilize ventilation (Fig. 197).
ASV devices from two manufacturers are available in the
United States (Table 192). They both adjust pressures with
a goal of stabilizing ventilation. The ResMed device (VPAP
Adapt SV) uses a goal of providing 90% of the recent average

IPAP pressure EPAP pressure

Pressure (cm H2O)

30
Max IPAP setting
20

10
Min EPAP setting
0
0 1 2 3 4 5 6 7
Time (hrs)

FIGURE 196 An overnight pressure-versus-time tracing is shown for a patient using autobilevel positive airway
pressure (PAP) with a minimum expiratory positive airway pressure (EPAP) of 6 cm H2O and a maximum inspiratory
airway pressure (IPAP) of 25 cm H2O. The 90th percentile IPAP and EPAP pressures were 19.2 cm H2O and 16.2 cm H2O,
respectively. The average IPAP and EPAP values were 14.6 cm H2O and 11.8 cm H2O, respectively. From Kakkar RK, Berry
RB: Positive airway pressure treatment for obstructive sleep apnea. Chest 2007;132:10571072.

Inspiration
Cflow

Chest

ABD

SpO2
96 95 98 97 95 96 96
Cpress
20
10
0
Lateral position, ASV adapting

FIGURE 197 The adaptive servoventilation (ASV) device responds to variation in flow by increasing pressure support (PS) when flow and ventilation are
DaneshGroup.com
low and decreasing PS when flow is high. ABD = abdomen; Cflow = flow signal from the PAP device; Cpress = delivered pressure; SpO2 = pulse oximetry.
318 Chapter 19 Positive Airway Pressure Treatment

TABLE 192
Adaptive Servoventilation Devices
BRAND NAME RESMED ADAPT SV PHILIPS-RESPIRONICS AUTO BIPAP SV ADVANCED
Target 90% of previous average ventilation 90% of average peak flow (moving time window)
(moving time window)
EPAP EPP titrated manually EPAP automatically adjusted between EPAPmin and
To prevent upper airway obstruction EPAPmax
IPAP Max available 25 cm H2O Max pressure up to 30 cm H2O
Varies to deliver optimal PS IPAP varies to deliver PS between PSmin (can be 0)
Limits: PSmin to PSmax depending on to PSmax
EPP and maximum machine pressure PSmax constrained by maximum pressure and
PSmin 3 cm H2O current level of EPAP
Backup rate Automatic Auto rate
Approximately 15 breaths/min Fixed rate
Inspiratory time Automatic Automatic in auto rate mode
Set in manual rate mode (default 1.5 sec)
Recommended EPP = 4 cm H2O EPAPmin = 4 cm H2O
initial settings PSmin 3 cm H2O EPAPmax = 15 cm H2O
PSmax 10 cm H2O PSmin = 0
PSmax = 20
Max pressure = 25 cm H2O
Rate: auto
If rate set, use IPAPtime (I-time) = 1.5 sec
BiPAP = bilevel positive airway pressure; EPAP = expiratory positive airway pressure; EPP = EPAP; IPAP = inspiratory positive airway pressure; PS = pressure support;
SV = servoventilation.

ventilation (moving time window). With low tidal volume,
the PS increases, and with high tidal volume, the PS decreases.
An automatic backup rate triggers an IPAP/EPAP cycle if
central apnea is present (default 15 breaths/min). The tech-
nologist can only adjust the EPAP (termed EPP for this
brand of ASV). The PS is constrained by PSmax (10 cm
H2O is recommended) and the maximum IPAP is con-
strained by maximum pressure of 25 cm H2O.
The Philips-Respironics device (BiPAP Auto SV) targets
90% of the previous average peak flow (moving time average)
and has a within-breath adjustment capability. The IPAP
increases to provide PS between the limits of PSmin and
PSmax as needed to augment flow. The EPAP is adjusted to
maintain an open upper airway. The BiPAP Auto SV pro-
vides CPAP = EPAP if ventilation is stable and if PSmin = 0
(default setting). The backup rate can be set at a fixed rate
(or rate = 0) but usually the autorate is used. The autorate
provides a background rate of 8 to 10 breaths/min or higher
depending on previous percentage of patient-triggered
breaths. The rate is increased based on current cycle time and
EPAPtime (time since start of the EPAP cycle). If a fixed
backup rate is specified, an IPAPtime (or inspiratory time
[Ti]) must also be specified. The Ti is usually 1.2 to 1.6 sec
(recommended 1.5 sec). However, in the autorate mode, the
device automatically selects a Ti. If a fixed backup rate is
used, the manufacturer suggests starting at 2 breaths/min
below the spontaneous rate (minimum 810). The latest
version of the BiPAP Auto SV device, called BiPAP Auto SV
advanced, can automatically titrate EPAP with algorithms
similar to the one used for APAP devices to overcome any
obstructive component of breathing. The clinician specifies
EPAPmin and EPAPmax and the device titrates EPAP
between those settings. The initial EPAPmin = 4 cm H2O
unless it is known or suspected that CPAP higher than 10 cm
H2O is needed to maintain an open upper airway. In that
case, EPAPmin of 6 to 8 cm H2O is used. For example, a
previous titration showed that CPAP of 12 cm H2O was
needed during REM sleep.
Of note, patients with CSB-central apnea and CompSA
(including patients on narcotics) can also be treated with
BPAP in the ST mode. One study comparing BPAP-ST with
ASV in patients with central apnea and CompSA found ASV
to result in only a slightly lower AHI than BPAP-ST.34
However, stabilizing ventilation with BPAP-ST in this situa-
tion often requires a high backup rate (with a high propor-
tion of machine-triggered breaths). Higher PS is usually
needed to deliver a machine-triggered breath because the
patient does not assist with inspiration. It is preferable to
have the patient trigger the majority of breaths because
timing and effective ventilation are usually better. Thus, ASV
is generally preferable because, if ventilation is stabilized, a
majority of the breaths will be patient-triggered. However,
there are individual patients who may respond better to
BPAP-ST.
An important concept when using ASV is that of
closed airway central apnea. As noted previously, during
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 Chapter 19 Positive Airway Pressure Treatment 319

F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG

Cflow

D
Chest

ABD

SpO2

Cpress CPAP for stable flow IPAP incr for low flow Machine triggered breaths
A B C
20
10
0
ASV IPAPmax = 20 EPAP = 10 180 second window 120 V
PSmin = 0

FIGURE 198 A patient with Cheyne-Stokes breathing on a BPAP Auto SV device. A, Continuous positive airway pressure (CPAP) is delivered as pressure support
(PS) equals PSmin (here = 0) and flow is high. B, PS increases as flow is low. C, Machine-triggered breaths during a central apnea. D, The machine-triggered PS
was not effective due to a closed upper airway. An increase in expiratory positive airway pressure (EPAP) is needed. ABD = abdomen; ASV = adaptive servoventilation;
Cpress = delivered pressure; ECG = electrocardiogram; IPAP = inspiratory positive airway pressure; SpO2 = pulse oximetry. From Brown LK: Adaptive servo-
ventilation for sleep apnea: technology, titration protocols, and treatment efficacy. Sleep Med Clin 2010;5:433.

central apnea, the upper airway may close.31 For example,
during a mixed apnea, the airway has closed during the
central portion. If a closed airway central apnea occurs, the
machine-triggered PS will not effectively deliver flow (or
tidal volume). In this case, higher EPAP is needed (Fig. 19
8). ASV was not specifically designed for patients with noc-
turnal hypoventilation. However, some patients with
CompSA due to narcotics have both hypoventilation and
instability in breathing. A higher PSmin (4 cm H2O) may
be needed if the arterial oxygen saturation (SaO2) remains
low but breathing is regular. Another situation in which
PSmin greater than 0 is useful is the pressure-intolerant
patient. Rather than using EPAP of 16, one could use an
EPAP of 14 and a PSmin of 4. Thus, the device would deliver
a basal pressure of 18/14 cm H2O with higher IPAP as needed
to stabilize ventilation. This example also illustrates that if a
patient requires high EPAP, quite high IPAP values may be
needed to deliver an adequate PS.
VOLUME-TARGETED BPAP
Recently, volume-targeted bilevel positive airway pressure
(VT-BPAP) has been developed in which the IPAP-EPAP
difference is automatically adjusted to deliver a target tidal
volume.3942 VT-BPAP has the potential advantage of
automatically varying the PS to deliver a targeted tidal
volume if the condition of the patient changes. For example,
if respiratory muscle strength declined and the tidal volume
decreased, the device would deliver higher PS to return the
delivered tidal volume to the targeted level. VT-BPAP can be
used in the S, ST, or T mode. Relatively few studies on
VT-BPAP devices have been published. To date, only one
VT-BPAP device is available in the United States (Average
Volume Assured Pressure Support [AVAPS], Philips-
Respironics). Storre and colleagues39 compared BPAP and
AVAPS (both in the ST mode) using a randomized, cross-
over trial in patients with OHS. AVAPS resulted in a slightly
higher ventilation and lower arterial partial pressure of
carbon dioxide (PaCO2) without any better sleep quality or
quality of life measures compared with BPAP-ST. Using the
same device, Ambrogio and associates40 studied an assort-
ment of patients with chronic alveolar hypoventilation who
were stable on BPAP support. A validation night preceded
the study nights to ensure the BPAP settings were adequate
and to provide guidance for the AVAPS settings. Patients
then were studied on BPAP or AVAPS in random order. On
AVAPS, the minute ventilation was greater than on BPAP but
sleep quality was comparable between the two NPPV modes.
Using a different VT-BPAP device, Janssens and coworkers41
monitored patients with the OHS using either BPAP or
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320 Chapter 19 Positive Airway Pressure Treatment
VT-BPAP for one night each in random order. Sleep quality
was worse but nocturnal transcutaneous partial pressure of
carbon dioxide (TcPCO2) was slightly lower on VT-BPAP. It
is possible that patients might have exhibited better sleep
quality after a longer period of adaptation to the VT-BPAP.
Jaye and colleagues42 compared BPAP-ST with an autotitrat-
ing bilevel ventilator (autoVPAP) in patients with stable
neuromuscular and chest wall disease with nocturnal
hypoventilation and found autoVPAP to produce compara-
ble control of nocturnal oxygenation without compromising
sleep quality. The mean nocturnal TcPCO2 was higher with
autoVPAP, although the difference was unlikely to be clini-
cally significant. AutoVPAP (ResMed, Poway, CA) is not
currently available in the United States. These studies suggest
VT-BPAP can be effective, but the role of VT-BPAP in the
NPPV treatment of patients with chronic alveolar hypoven-
tilation syndromes remains to be determined.
When VT-BPAP is used, the purpose of a PSG PAP titra-
tion is to select a level of EPAP that eliminates obstructive
events (obstructive apnea and hypopnea) and document that
the device does deliver adequate tidal volumes. According to
the manufacturers recommendations, a target tidal volume
of 8 cc/kg (based on ideal body weight) is selected. Initial
settings are EPAP = 4 cm H2O, IPAPmin = EPAP + 4 cm
H2O, and IPAPmax = 25 to 30 cm H2O. If VT-BPAP is used
in the ST or T mode, the backup rate and Ti must also be
specified. A default Ti (IPAPtime) of 1.5 seconds is recom-
mended by the manufacturer.
FIGURE 199 A, C-Flex. The pressure drops at the start of
exhalation (the amount depends on expiratory flow and the C-Flex
setting, 1, 2, or 3) but returns to the set continuous positive airway
pressure (CPAP) pressure at end-exhalation. B, Aflex. (1) The
inspiratory pressure autoadjusts as per autoadjusting positive
airway pressure (APAP), (2) smoothing of transition from inspiration
to exhalation, (3) expiratory pressure relief similar to C-Flex. The
end-expiratory pressure is 2 cm H2O below the inspiratory pressure
(pressure difference). A, From Mulgrew AT, Cheema R, Fleetham J,
et al: Efficacy and patient satisfaction with autoadjusting CPAP with
variable expiratory pressure vs standard CPAP: a two-night
randomized crossover trial. Sleep Breath 2007;11:3137.
A (1,2,3)
Aflex
B
COMFORT MEASURES
Ramp
Most PAP devices, with the exception of certain APAP
devices, allow the patient to trigger the ramp option. In the
ramp option, the pressure starts at a preset levelusually a
low level of CPAPand then slowly increases to the treat-
ment pressure (CPAP) over the set ramp time. Some APAP
devices have a settling time at a low pressure before the
device starts autoadjusting pressure. The ramp option is
appealing and can be used during midnight awakenings to
help patients return to sleep. However, no study has shown
that the ramp option increased adherence.
Flexible Pressure
Two manufacturers of PAP devices have developed flexible
PAP in an attempt to improve patient comfort and adher-
ence. Some PAP devices manufactured by Philips-Respironics
provide several comfort options (Cflex, Cflex+, and Aflex)
(Fig. 199). ResMed devices offer expiratory pressure relief
(EPR). However, there are no convincing data that any of
these options improve adherence in unselected patients. In
Cflex, expiratory pressure drops at the start of exhalation but
returns to the set CPAP at end-exhalation. The amount of
drop (Cflex 1, 2, 3) is determined by a proprietary algorithm.
In general, there is a greater pressure drop for greater flow
during exhalation. Cflex is available on APAP devices as well
Typical patient flow Flow
Inspiration
Expiration
CPAP with C-Flex Pressure
Inspiration
Expiration
Flow
1
2 Pressure
difference
Pressure
3
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 Chapter 19 Positive Airway Pressure Treatment 321

as CPAP. Cflex+ adds a smoothing of the transition from introduced. One study suggested that use of humidity is
inhalation to exhalation. Aflex is a form of APAP that pro- associated with an increase in risk of infectious complica-
vides a 2 cm H2O lower end-expiratory pressure than the tions53 that can be reduced with use of a filter.54 There is an
inspiratory pressure (in addition to the features of Cflex+). occasional patient with recurrent sinus infections who seems
For both BPAP and autoBPAP devices, a form of expiratory to do better without humidificationbut the etiology of this
pressure relief is available (Biflex). The technology provides improvement is unclear.
a smoothing of transition from IPAP to EPAP as well as Studies determining whether HH improves either accep-
expiratory pressure relief during the EPAP cycle (Biflex 1, tance of CPAP after titration or long-term adherence to
2, 3). CPAP treatment have found conflicting results. Massie and
ResMed devices provide EPR and drop the pressure associates55 studied patients who received either HH or cool
during the start of exhalation pressure by 1, 2, or 3 cm H2O humidity for 3 weeks (random order), a 2-week washout
(EPR 1, 2, 3). The EPR can be used full time or only during period of no humidity, and 3 weeks of the alternative humid-
the ramp period. EPR is not available with ResMed APAP ity. Patients on HH had about 1 2 hour greater objective
devices. adherence than those on no humidity (Table 193). However,
An initial study found that flexible PAP improved adher- several other studies have not found an improvement in
ence by about 1 2 hour using a cross-over design.43 A number adherence5661 with the use of HH for PAP treatment. Other
of subsequent studies in patients on CPAP4448 or APAP49
have not found an increase in adherence. The mode can still
be useful for individual patients who find CPAP difficult to
tolerate. Conversely, some patients actually prefer CPAP to TABLE 193
flexible PAP. Effect of Humidity on Outcomes
COLD
Humidification HEATED PASSOVER NO
HUMIDITY HUMIDITY HUMIDITY
Today, most PAP devices come with the option of an inte-
grated heated humidification system. They can be used in the Usage (hr/night) 5.52 2.1* 5.15 1.9 4.93 2.2
cool humidity mode if desired. Heated humidity (HH) can Epworth 6.2 3.8 7.2 4.8 6.7 3.9
deliver a greater level of moisture than cool humidification Sleepiness
and may be especially useful in patients with mouth leak or Scale
nasal congestion. Mouth leak can cause a dramatic fall in Feeling on 74 15.9 68.9 23.4 62.0 23.4
relative humidity50 (Fig. 1910) and a loss of humidity from awakening
the upper airway/CPAP system, thus drying the nasal or oral
Satisfaction 73.9 19.1 72.9 22.6 62.3 27.6
mucosa. Drying of the nasal mucosa increases nasal resis- with CPAP
tance and this is minimized by use of HH.51,52 HH is more
effective than cool at delivering moisture. The level of humid- Adverse side 4.9 3.3 6.2 3.8 6.5 4.9
ity can be adjusted by the patient to meet variable needs. An effects score
occasional patient will prefer cool humidity (heat turned off) *P < .008.

P < .05. Heated humidity versus no humidity.
or no humidity at all. Adequate cleaning of the humidifier
P < .05. Cool humidity versus no humidity.54
chamber and hoses does require extra patient effort. A Data from Massie CA, Hart RW: Clinical outcomes related to interface type in
number of technologic advances for adjusting humidity to patients with obstructive sleep apnea/hypopnea syndrome who are using
continuous positive airway pressure. Chest 2003;123:11121118.
prevent rain-out in the tubing and mask have recently been

FIGURE 1910 This tracing shows a fall in the relative humidity at the
nasal mask during mouth leaks (leak detected by an oral thermistor).
100 Heated humidification minimized but did not eliminate the fall in relative
humidity. CPAP = continuous positive airway pressure. From Martins de
Araujo MT, Vieira SB, Vasquez EC, Fleury B: Heated humidification or face mask
Relative humidity (%)

Leaks
to prevent upper airway dryness during continuous positive airway pressure
therapy. Chest 2000;117:142147.
50

Leaks

0
Nasal CPAP Nasal CPAP + Humidification

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322 Chapter 19 Positive Airway Pressure Treatment
investigations could not document a benefit from the pro-
phylactic use of HH for titration. A criticism of these
studies is that patients with baseline nasal congestion or
dryness were not targeted. It seems reasonable to use humid-
ity in patients with complaints of nasal congestion or mouth
breathing at baseline. Certainly, in some patients, use of HH
is crucial, and in others, it may improve satisfaction. Rain-
out in the tubing and the mask is a significant problem for
some patients. Lowering the CPAP unit to a level below the
bed (water flows back into the humidifier chamber by
gravity), reducing the humidity setting, or using a tube
insulator may help. New technology recently available
adjusts the humidifier setting based on room temperature
and relative humidity. However, it is not clear that this tech-
nology will improve adherence. In the practice parameters
for PAP treatment (Appendix 191), use of HH is recom-
mended to improve CPAP utilization.3 In the clinical guide-
lines for titration, having HH available for titration was
recommended.62
Interfaces
When CPAP devices became available commercially, the first
interfaces were nasal masks. Today, a large variety of inter-
faces is available (Fig. 1911), but it may still be difficult to
obtain a good mask fit. Nasal pillow masks are often better
tolerated than traditional nasal masks by patients with claus-
trophobia and are useful in patients with a mustache or
edentulous patients who have no dental support for the
upper lip.63 It is essential to use a size of pillow large enough
to provide a good seal. A wide variety of nasal masks with
gel or air cushion interfaces is available. For patients who
FIGURE 1911 Positive airway pressure (PAP) interface options. Left, A nasal pillows
mask (Swift LT for her by ResMed, Poway, CA). Right, A full face mask (Quattro by
ResMed, Poway, CA).
have severe nasal congestion or open their mouths during
PAP treatment, oronasal (full face masks)64,65 and oral inter-
faces66,67 are available. Oronasal masks have to seal over a
large area, and this makes finding a good fit very difficult in
some patients. In edentulous patients, oronasal masks may
also compress the soft tissues. Patients tend to overtighten
masks, and this can cause damage to the nasal bridge or
actually impair the ability of the mask to seal. Often, a trial
of several masks is needed to find one that patients can use
comfortably. This is a challenge because insurance providers
typically will pay for only one mask every 3 to 6 months. This
is one situation in which trying several different types of
mask in the sleep center before the titration can be very
useful. Adequate care and replacement of masks are also
essential to maximize their ability to seal. If the patient gets
up to use the bathroom during the night, we encourage
disconnection of the hose from mask rather than taking off
the mask. Masks that are removed in the middle of the night
are often not replaced.
INDICATIONS FOR PAP TREATMENT
Important elements of the AASM practice parameters for the
use of PAP and APAP are listed in Appendix 191. Treat-
ment with PAP is indicated for patients with moderate to
severe OSA (with or without symptoms).2,3 PAP treatment is
an option for patients with mild OSA who are symptomatic
and choose PAP over other treatment options (upper airway
surgery or an oral appliance). The Centers for Medicare and
Medicaid Services (CMS) requirements for PAP reimburse-
ment are specified in the National Carrier Determination
240.4.68 Patients must be diagnosed with either a PSG or a
home sleep test (HST) that follows Medicare requirements
for those evaluations (discussed in Chapter 13). CPAP treat-
ment is reimbursed for an initial 12-week period if the AHI
is 15/hr or greater with or without symptoms or if the AHI
is 5/hr or greater but less than 14/hr if certain symptoms
(excessive daytime sleepiness, impaired cognition, mood
disorders, or insomnia) or certain disorders (hypertension,
ischemic heart disease, or history of stroke) are present. For
continued payment after that period, adequate objective
adherence must be documented. For at least 1 month during
the qualifying period, CPAP must be 4 hours for 70% of
nights. A face-to-face evaluation of the patient by the physi-
cian ordering CPAP and documentation of a benefit from
treatment are also required. The exact requirements vary
with different local carrier determinations (LCDs) (Appen-
dix 192). Most other health insurance providers follow
similar guidelines.
As noted in Chapters 18 and 20, the initial treatment for
most children with OSA is tonsillectomy and adenoidec-
tomy. However, residual sleep apnea is present in a signifi-
cant portion of patients.69 The clinician must then decide on
further treatment recommendations based on the residual
AHI and symptoms. Excessive daytime sleepiness, poor
school performance, behavioral issues, and cardiovascular
consequences should all be considered. PAP is an effective
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option provided that both the parents and the patient accept
this treatment. The exact AHI cutoff is not well defined, but
many pediatricians consider a residual greater than 5/hr as
indicating significant OSA in children and an indication for
CPAP treatment. Those less symptomatic patients with an
AHI between 1 and 5 are in a gray zone and treatment must
be individualized. Starting CPAP in children often requires
periods of adaptation to a mask before a titration can be
attempted.62,70 Other options include weight loss, dental pro-
cedures, or intranasal steroids and leukotriene modifier
therapy.71
ADHERENCEDEFINITIONS
AND MEASUREMENT
Despite the excellent efficacy of PAP devices for reducing the
AHI, the actual effectiveness is much lower. For example, if
CPAP reduces the AHI from 40 to 5/hr but is used only 50%
of nights, the mean AHI has only been reduced to 25/hr.
Monitoring PAP adherence at one time involved looking at
the run time meter on devices. Then the devices began to
record both blower hours and time at pressure (actual use).
Today, PAP machines have both internal memory and
removal memory (smart cards, memory sticks, or disks).
The removable media can store extensive information on
adherence and patterns of use. The recorded device informa-
tion can be assessed by direct machine interrogation (inter-
nal memory) or transferring of information on removable
media to a computer. Some devices when attached to a
modem can send information to a central location and phy-
sicians can obtain ongoing data on a patient. Other devices
can communicate with a central location using wireless
technology. The data obtained from PAP devices often
includes useful information on leak as well as an estimate of
the residual AHI. Detailed daily information can show
important patterns, for example, consistent mask removal at
5 AM. As discussed later, it has been shown that the pattern
of use is established early and that objective adherence
(not patient report) is essential to guide treatment. Data
via modem or wireless communication can provide infor-
mation during the critical first weeks of use without requir-
ing the patient to come to a clinic or a durable medical
equipment office.
Adherence rates are defined in many ways. Most devices
compute the percentage of days used, the average use all days
(averaging in 0s for days not used), average nightly use (days
used), and the percentage of nights used 4 hours. An early
paper reporting measurement of objective adherence by
Kribbs and coworkers72 defined regular users as those who
used CPAP at least 4 hr/day on at least 70% of nights. In their
study, only 46% of patients met this criterion.
PAP Adherence in Large Studies
There has been a tremendous variability in the reported rates
of PAP adherence. This is due to a number of factors includ-
ing different populations (moderate to severe OSA vs. all
Chapter 19 Positive Airway Pressure Treatment 323
TABLE 194
Factors Predicting Good or Worse Adherence
WORSE
GOOD ADHERENCE ADHERENCE NO EFFECT
More sleepy Spouse referred Level of
Higher AHI Not sleepy pressure
Greater perception High nasal Pressure
of benefit resistance technology
Good early Poor early minimal if
adherence adherence any effect
AHI = apnea-hypopnea index.
patients), different definitions of adherence, different length
of follow-up, and different algorithms of initiating PAP treat-
ment and following patients. One of the largest studies of
long-term adherence with nasal CPAP reported only 68% of
patients were still using CPAP at 5 years.73 Ppin and col-
leagues74 found 79% of patients using CPAP for longer than
4 hours on 70% of nights at 3 months. Sin and coworkers75
followed patients with an AHI greater than 20/hr and found
greater than 85% were using the device longer than 3.5 hr/
night at 6 months. Kohler and associates76 found that 81% of
patients were using CPAP at 5 years.
Factors Influencing Adherence and Importance
of Early Adherence
Several studies have addressed the factors associated with
good versus poor PAP adherence (Table 194). In general,
the factors identified to date explain relatively little of the
large variance in CPAP acceptance and adherence.73,74,76,77
The level of pressure does not seem to be important. Finding
an acceptable interface is often the biggest challenge in
getting patients to adhere to PAP treatment. However, there
is no evidence for the superiority of any type of interface.
Although a great deal of effort is spent in intervening for side
effects, the presence or absence of side effects does not seem
to be a major determinant of PAP use.77 Patients may be
willing to tolerate side effects if there is a significant improve-
ment in pretreatment symptoms. Factors favoring better
adherence include symptomatic daytime sleepiness, good
response in sleepiness to treatment, and to a lesser extent
disease severity (AHI). In one study a high arterial oxygen
desaturation index predicted good adherence.76 Poor prog-
nostic factors include spouse referral and high nasal resis-
tance.75,78 Whether CPAP treatment follows a split night
(diagnostic/PAP titration) or separate diagnostic and PAP
titration studies does not seem to affect PAP adherence.
Early adherence is a good predictor of long term PAP use.
In a study of 32 patients followed for 9 weeks, the nightly
duration of use differed between compliant and noncompli-
ant patients by the fourth night of use.79 Budhiraja and col-
leagues80 found that long-term adherence to CPAP can be
predicted as early as 3 days after CPAP initiation.
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324 Chapter 19 Positive Airway Pressure Treatment
70
60
% with normal values
50
40
30
20
10
FOSQ ESS MSLT
0 PAP help line
2 >2<4 4,<5 5<6 6<7 7
Hours of nightly CPAP use
FIGURE 1912 Cumulative proportion of participants obtaining normal threshold
values on the Epworth Sleepiness Scale (ESS), multiple sleep latency test (MSLT), and
Functional Outcomes of Sleep Questionnaire (FOSQ). CPAP = continuous positive airway
pressure. From Weaver TE, Maislin G, Dinges DF, et al: Relationship between hours of
CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep
2007;30:711719.
How Much Adherence Is Enough?
Weaver and associates81 studied patients before and after 3
months of therapy and correlated objective adherence with
improvement in functioning (Fig. 1912). Thresholds above
which further improvements were less likely relative to
nightly duration of CPAP use were identified for Epworth
Sleepiness Scale score (4 hr), multiple sleep latency test
(6 hr), and Functional Outcomes Associated with Sleepiness
Questionnaire (7.5 hr). Thus, as usage increases, subjective
sleepiness, then objective sleepiness, and last, quality of
life measures improve. The amount of necessary usage
depends on what outcome is being evaluated. As noted
above, the current Medicare guidelines state that devices will
be reimbursed after 12 weeks only if objective adherence
for a period of 1 month shows 4 hours of use for 70% of
nights and the treating physician documents in a face-to-face
meeting that the patient is benefiting from PAP treatment
(see Appendix 192). However, many patients require much
greater than 4 hours nightly use to experience a resolution
of excessive sleepiness. Campos-Rodriguez and coworkers82
followed a historical cohort of 871 patients with OSA for a
mean of 48 months. Five-year cumulative survival was
highest in the group of patients who used PAP therapy more
than 6 hours per night on average (96.4% survival) compared
with patients who used PAP from 1 to 6 hours per night
(91.3% survival) and patients who used PAP less than 1 hour
per night (85.5%). The same group conducted a prospective
cohort study of 55 patients with hypertension.83 Patients with
average use greater than 5.3 hr/day and hypertension at
entry to the study had a drop in mean arterial blood pressure
of about 4 mm Hg.
Interventions to Improve Adherence
The literature on this subject is somewhat difficult to
interpret because most programs use a number of interven-
tions to try to improve adherence6 (Table 195). Although
TABLE 195
Methods to Improve Positive Airway Pressure
Adherence
Education about OSA and PAP by staff, video, printed
information
Involvement of significant other/spouse
Subsequent mask and headgear adjustment or change as
needed
Unsolicited telephone follow-up
Early interventions for side effects and concerns
Objective monitoring of adherence
Early and regular clinic visits
OSA = obstructive sleep apnea; PAP = positive airway pressure.
education about OSA and PAP treatment is recommended,
there is no evidence that this dramatically improves adher-
ence.84 Comprehensive programs of education (patient and
bed partner), early contact, and interventions,85 a simple
CPAP help line,86 or group education87 have improved adher-
ence in some studies. Cognitive behavioral interventions
have shown promise.88,89 Timely interventions for side effects
and discomforts would also seem reasonable, although not
proved to improve adherence. Table 196 presents common
problems and possible solutions. Finding a comfortable and
well-fitting mask interface is one of the biggest challenges in
PAP treatment. Proper sizing and mask adjustment are
essential and should be checked at every visit to the physi-
cian or respiratory therapist providing PAP support. If neces-
sary, a different mask type could be tried. For mouth leaks,
the addition of a chin strap, higher humidity, or a full face
mask is an option. Sometimes, a leak will respond to slight
lowering of pressure or switch from CPAP to BPAP if all else
fails. Nasal pillows may help deal with claustrophobia. Unin-
tentional mask removal may indicate a leak or inadequate
pressure. Nasal congestion can be addressed with nasal ste-
roids, antihistamines, increased humidity, or reduced mask
leak. Rhinitis/rhinorrhea may respond to nasal ipratropium
bromide. For pressure intolerance, use of a lower pressure,
addition of flexible CPAP, a change to APAP or BPAP, and
education about using the ramp are all options.
Hypnotics, Alcohol, and CPAP
Patients with both insomnia and OSA pose a difficult
problem. In addition, some patients who normally have no
problems with insomnia will have problems falling asleep or
staying asleep on CPAP. Some clinicians have been hesitant
to prescribe hypnotics, believing that this may reduce the
effectiveness of CPAP. There has also been a concern that the
use of alcohol could increase the required level of CPAP
above that demonstrated to be effective in the sleep center.
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 Chapter 19 Positive Airway Pressure Treatment 325

TABLE 196
Interventions for Common Positive Airway Pressure Treatment Side Effects
POSITIVE PRESSURE SIDE EFFECTS INTERVENTIONS
MASK SIDE EFFECTS
Air leaks Proper mask fitting
Conjunctivitis Proper mask application (education)
Discomfort Different brand/type of mask
Noise
Skin breakdown Avoid overtighteningintervene as above for leaks
Alternate between different mask types
Nasal prongs/pillows
Tape barrier for skin protection
Mouth leaks Treat nasal congestion if present (see below)
Mouth dryness Chin strap
Heated humidity
Full face (oronasal) mask
Consider BPAP, flexible PAP, lower pressure, APAP
Mask claustrophobia Nasal pillows/prongs interface
Desensitization
Unintentional mask removal Low-pressure alarm
Consider increase in pressure
NASAL SYMPTOMS
Congestion/obstruction Nasal steroid inhaler
Antihistamines (if allergic component)
Nasal saline
Humidification (heated)
Full face (oronasal) mask
Nighttime topical decongestants (oxymetazoline) as a last resort
Epistaxis Nasal saline
Pain Humidification (heated)
Rhinorrhea Nasal ipratropium bromide
OTHER PROBLEMS
Pressure intolerance Ramp
Flexible PAP
BPAP
APAP
Lower prescription pressure temporarilyaccept higher AHI
Lower pressure + adjunctive measures (elevated head of bed, side sleeping position,
weight loss)
Aerophagia/bloating BPAP, flexible PAP, reduce pressure
AHI = apnea-hypopnea index; APAP = autoadjusting positive airway pressure; BPAP = bilevel positive airway pressure; PAP = positive airway pressure.

However, one study found that moderate alcohol consump-
tion near bedtime did not impair the efficacy of CPAP.90
Another study found that zolpidem, a commonly used hyp-
notic, did not impair efficacy of a given level of CPAP.91
Conversely, it has been hypothesized that using a hypnotic
might improve adherence to PAP in some patients. A study
by Bradshaw and colleagues92 using zolpidem did not find an
improvement. In contrast, Lettieri and associates93,94 found
improvement during CPAP titration (sleep quality) and
long-term adherence with eszopiclone (a hypnotic with a
longer duration of action that zolpidem). It is possible that a
longer-acting medication is needed to improve CPAP adher-
ence. Although routine use of a hypnotic cannot currently
be recommended, at least temporary use of a hypnotic
should be considered if insomnia is a major obstacle to
CPAP use.
CPAP/BPAP TITRATION FOR OSA
A PSG is the standard method PAP for titration and is
usually accomplished either as the second part of a split
study or during an entire night after a previous diagnostic
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326 Chapter 19 Positive Airway Pressure Treatment

study. The American Academy of Sleep Medicine (AASM)
practice parameters for the use of PSG provide guidance
about when a split study is acceptable.95 A split study is rec-
ommended only if the AHI is greater than 40/hr and 2
hours of monitoring have occurred. In addition, 3 hours of
PAP titration is the minimum acceptable duration. If an
adequate titration is not obtained, a repeat PSG titration is
indicated. Of note, these recommendations for a split study
are based on limited data and some sleep centers have more
lenient criteria for use of a split study. CMS guidelines for
qualifying a patient for PAP formerly required at least 2
hours of recorded sleep in the diagnostic portion of a split
study. This requirement has been dropped. If less than 2
hours of sleep are recorded, the minimum number of apneas
and hypopneas must equal the number that would have
been required if 2 hours of sleep had been recorded68 (see
also Appendix 192). For example, to meet a cutoff of an
AHI of 15/hr, a total of 30 apneas and hypopneas must be
recorded. Recently, Clinical Guidelines for the Titration of
BPAP and CPAP for Obstructive Sleep Apnea were written
by a task force of the AASM and approved by the board
of directors.62 Excerpts from the titration guidelines are
discussed later. The reader is referred to this informative
document.
General Titration Considerations
A number of general recommendations for PAP titration are
listed in Table 197. Before PAP titration, the patient should
be educated about OSA, PAP treatment, and the PAP titra-
tion process.3,62 They should be given mask interface options.
They should try on one or more interfaces while breathing
on low pressure (CPAP practice). If a split study has been
ordered, these events should take place before any
diagnostic monitoring begins. A number of interfaces
should be available (nasal, oronasal, oral, pillows) including
masks in sizes suitable for children if a child is being studied.
HH should be available as well as a source of supplemental
oxygen.
Pediatric Considerations
PAP titrations in children require some extra considerations.
Children are often given a mask to play with and try on
during the day for a week before scheduled studies. The
child should be desensitized to the mask during the day by
wearing it for increasing periods of time while engaging in
a fun activity (e.g., watching a favorite video). Split-night
studies are not recommended for children. If the child
without previous mask desensitization undergoes a split-
night study, you may frighten the child and this will make
subsequent CPAP use unlikely. Pediatric size masks should
be available. Durable medical equipment providers and sleep
technologists skilled and willing to provide care for pediatric-
age patients should be utilized.62,96 Studies have shown that
structured behavioral interventions help with compliance
(graduated exposure, positive reinforcement, dealing with
escape and avoidance behavior, and praising distracting
activities that allow the child to wear a mask).70,97,98
Monitoring during Positive-Pressure Titration
Most positive-pressure devices used in the sleep disorders
center provide several analog or digital outputs that can be

TABLE 197
Positive Airway Pressure Titration (Equipment, Patient Preparation, and General Recommendations)
All potential PAP candidates (PAP
titration and potential split titration)
Monitoring
Interfaces
High leakone higher than expected
for a given interface and pressure
Heated humidity available
Treatment emergent central apneas
Repeat PAP titration
BPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; IPAP = inspiratory positive airway pressure; PAP = positive airway pressure;
RERAs = respiratory effortrelated arousals.
PAP education.
Mask fitting, try several interfaces.
Acclimatization period with low pressure.
Airflow monitored from machine flow signal.
RERAs identified by flattening of the machine flow signal associated with arousal.
Leak, machine pressure recorded if possible.
Nasal, full face (oronasal), nasal pillows, oral should be available.
Interfaces in pediatric sizes if children are studied.
Mask adjustment, refit, change.
Used for nasal congestion or dryness
Let the patient settle downif they reach stage N3, central apneas may stop.
Try lowering CPAP or IPAP.
Do not switch from CPAP to BPAP as a response to central apneas unless a backup
rate is used.
Less than 3 hours during PAP titration of split study.
Good or acceptable titration results NOT obtained.
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TABLE 198
Monitoring during Positive Airway Pressure or Noninvasive Positive Pressure Ventilation Titration
PARAMETER SENSOR REASON
Airflow PAP/NPPV device output (accurate internal flow Detection of apnea, hypopnea, and RERAs.
sensor).
Leak Leak estimate by PAP or NPPV device from accurate Total leak = intentional + unintentional leak
flow measurement. (some device output an estimate of
unintentional leak rather than total leak).
Snoring Piezoelectric sensor or microphone. Detection of snoring.
Pressure External pressure transducer or NPPV device signal Documentation of amount and pattern of
(internal pressure sensor). pressure delivery.
Chest and abdominal Respiratory inductance plethysmography. Differentiating central and obstructive
movement events, detection of paradox.
NPPV
Tidal volume NPPV device output (from integration of flow signal). Estimate of tidal volume.
Respiratory muscle Bipolar monitoring: use surface electrodes over the Absence or reduction in respiratory muscle
EMG diaphragm or intercostal muscles. EMG suggests adequate respiratory
muscle rest has been achieved.
PETCO2 Side stream via nasal cannula in nares under the Breath-by-breath estimate of PaCO2.
mask.
TcPCO2 Transcutaneous sensor. Estimate of trends in PaCO2.
EMG = electromyogram; NPPV = noninvasive positive pressure ventilation; PAP = positive airway pressure; PaCO2 = arterial partial pressure of carbon dioxide;
PETCO2 = end-tidal carbon dioxide pressure; RERAs = respiratory effortrelated arousals; TcPCO2 = transcutaneous carbon dioxide pressure.

Flow Flow FIGURE 1913 Total flow increases with pressure but
Total flow CPAP flow Leak Total flow CPAP flow Leak is separated into a variable component (continuous
Inspiration

60 lpm 60 lpm positive airway pressure [CPAP] flow) and a more

constant component (leak). The leak includes
intentional (mask orifice) and unintentional leak. Note
30 lpm 30 lpm that CPAP flow is also called machine flow, CFlow, or
Leak
PAP flow. Note that on higher CPAP, the total flow
0 0
increases (see Figure 1914) as the intentional flow
increases (even if unintentional leak does not increase).
CPAP 5 CPAP 15

recorded (Table 198).62 The total flow delivered by the
machine is measured by an accurate flow sensor in the PAP
device. Use of a thermal device under the mask to monitor
flow is not recommended. The total flow is then divided by
the device into two components (Equation 191) that are
supplied for monitoring: (1) the PAP flow (also known as
CPAP flow, Cflow, or machine flow), which varies with inspi-
ration and expiration, and (2) the leak (bias flow), which is
a fairly constant portion due to system leak (Fig. 1913). The
CPAP flow signal is used to score respiratory events (apneas,
hypopneas, or respiratory eventrelated arousals [RERAs]).
The same respiratory scoring rules defined by the AASM
scoring manual are utilized with the exception that there is
one flow signal rather than the usual two (oronasal thermal
flow and nasal pressure).99 The total leak is due to the inten-
tional leak (to prevent rebreathing) and unintentional leak
(Equation 192). All CPAP mask interfaces have a built-in
orifice system consisting of small holes to provide an inten-
tional leak that washes out exhaled CO2 from the mask and
prevents rebreathing. This intentional leak increases with the
amount of pressure and varies between different masks (Fig.
1914). The unintentional leak is due to mask or mouth leak
(in the case of a nasal mask). Leak is seen by the machine as
bias or constant baseline inspiratory flow onto which the
variations in patient flow is superimposed. The leak signal
provided by some devices is the total leak whereas others
provide an estimate of unintentional leak by subtracting the
expected leak given the mask and pressure (mask type must
be specified). Absolute values are less useful than relative
increases in leak.
Total flow = PAP flow + Leak Equation 191
Leak = Intentional leak +
Equation 192
Unintentional leak
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328 Chapter 19 Positive Airway Pressure Treatment

60
A The PAP flow signal provides not only an estimate of the
B magnitude of flow but also information from the inspiratory
50
flow contour. High upper airway resistance is manifested by
Leak rate (lpm)

C
40 a flattened profile100 (Fig. 1915). The normal profile is a
30 rounded one. Figure 1916 shows that the CPAP flow signal
is flat at a pressure of 7 cm H2O and snoring is present. These
20
findings suggest significant upper airway narrowing is still
10 present. An increase in CPAP results in a round signal shape
0 and cessation of snoring.
5 10 15 20 25 30 35 40 CPAP flow signals are usually either filtered or insuffi-
Pressure (cm H2O) ciently sampled to show snoring. Snoring can be detected by
FIGURE 1914 Intentional leak increases with pressure and depends on the mask
a snoring sensor placed on the neck or from pressure vibra-
type (A, B, or C). Information is available with each mask. tions in mask pressure. Nearly all sleep center PAP units will
also provide a signal of the machine pressure. This is the
pressure at the machine outlet and can differ slightly from
the set pressure (value entered by technologist). The actual

FIGURE 1915 The shape of the PAP

device flow signal changes with increased 14
upper airway resistance, becoming flattened
CPAP (cm H2O)

13
consistent with airflow limitation. Here, a
drop in continuous positive airway pressure 12
(CPAP; arrow) results in change of flow signal 11
and increased pressure gradient across the
10
upper airway (increased resistance). From
Condos R, Norman RG, Krishnasamy I, et al: 50
Total flow (l/min)

Flow limitation as a noninvasive assessment 40

of residual upper-airway resistance during 30
continuous positive airway pressure therapy of 20
obstructive sleep apnea. Am J Respir Crit Care 10
Med 1994;150:475480. 0
Press. esoph (cm H2O)

4
2
0
2
4
6 Resistance  12 Resistance  29

0 5 10 15 20 25 30
Time (seconds)

FIGURE 1916 Flattening in the continuous positive airway

pressure (CPAP) flow signal (arrow) suggests high upper airway
resistance, and this is consistent with the appearance of snoring. CPAP 7 cm H2O
Here, inspiration is associated with an upward deflection in flow.
After only 1 cm H2O increase in pressure, the CPAP flow signal is now CPAP flow
round and the snoring has stopped.
Snore

CPAP 8 cm H2O

CPAP flow

Snore

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 Chapter 19 Positive Airway Pressure Treatment 329

mask pressure may be somewhat lower during inhalation
and sometimes slightly higher during exhalation. Mask pres-
sure can also be directly measured by connecting the mask
to a pressure transducer. Actual mask pressure can then be
recorded.
PAP units also provide a leak signal that can be monitored
and recorded. Recording of the leak signal is useful for the
physician reviewing a PAP titration. The trend in the leak is
more useful than the absolute number. If the patient has not
moved and leak suddenly increases, this could be a hint that
mouth leak is occurring (assuming the patient is wearing a
nasal mask). Sometimes, an increase in leak can occur with
the onset of REM sleep. Relaxation in the facial musculature
can sometimes produce mask or mouth leaks. In Figure
1917, there is a sudden increase in leak in a patient wearing
a nasal mask and chin strap when there is a transition to
REM sleep. Because there was no change in pressure or body
movement, this suggests that mouth leak was present (con-
firmed by video monitoring). Observation using video
(zooming in) can show an open mouth or fluttering of the
lips during mouth leak. If the flow signal becomes truncated
during expiration, this means that part or all of flow during
exhalation is not sensed by the machine flow sensor (no flow
returning to the hose/device system) consistent with an expi-
ratory leak from either the mask or the mouth. If the patient
is wearing a nasal mask (which has not moved), the sudden
appearance of truncated expiratory flow (often associated
with vibration in the snoring sensor) is suggestive of expira-
tory mouth leak (Fig. 1918). The technician does not neces-
sarily have to intervene unless mouth leak is arousing the

C4-M1

O2-M1

E1-M2

E2-M1

Stage N2 Stage R
Chin

Mouth open

Cflow

SaO2
94%

60

CPAP 18
Leak

CPAP
12 cm H2O

FIGURE 1917 A 120-second tracing shows flow from the continuous positive airway pressure device (Cflow), leak, and the delivered pressure at the device outlet
(CPAP). The patient was wearing a nasal mask and chin strap. At the transition to stage R, a large increase in leak was noted. The patient was not noted to move but
video observation showed that one corner of his mouth had opened slightly. Note that the increase in leak signal lags behind the obvious change in flow that occurs
a few seconds earlier. Stage R is associated with muscle hypotonia. SaO2 = arterial oxygen saturation.
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330 Chapter 19 Positive Airway Pressure Treatment

Patient wearing nasal mask

2 tracings from REM sleep on CPAP of 10 cm H2O

Epoch 600
Snore

CPAP
flow

Epoch 602

Snore

CPAP
flow

Expiratory
vibration

Expiratory flow is truncated

Truncated expiratory flow clue that mouth leak is present

FIGURE 1918 A change in expiratory flow combined with expiratory snoring is suggestive of an expiratory leak. Compare the truncated
expiratory flow in epoch 602 with the normal expiratory flow in epoch 602. This is due to expiratory mask or mouth leak (if a nasal mask is
being used). This patient was using a nasal mask and subtle lip fluttering was noted on video. The expiratory flow is truncated because part
of the expiratory flow does not pass into the tubing (escapes from the system) and is not sensed by the device flow sensor. Inspiration is
upward. CPAP = continuous positive airway pressure; REM = rapid eye movement.

patient or preventing PAP from maintaining a patent
airway. If mouth leak is a problem, either using a chin strap
or an oronasal mask or lowering the pressure could be
considered.
Additional Monitoring for NPPV Titration
For NPPV titration, it is useful to record the tidal volume
signal from the PAP device that is derived from integration
of the flow signal (see Fig. 193).22 Tidal volume depends
both on flow and inspiratory time. Therefore, monitoring the
flow signal alone may not provide an accurate estimate of
ventilation. Some sleep centers that perform NPPV in
patients with neuromuscular disorders also record an inter-
costal electromyogram (EMG) or surface diaphragmatic
EMG with techniques similar to those for leg EMG. If the
signal decreases, tidal volume increases and respiratory rate
decreases; these changes suggest that adequate respiratory
muscle rest is being delivered by the current level of PS (Fig.
1919).101,102 In addition, some sleep centers record either the
end-tidal partial carbon dioxide pressure (PETCO2) or
TcPCO2.103,104 However, the exhaled gas sampled for the
PETCO2 measurement can be diluted by NPPV flow. A
common method is to use a small nasal cannula under the
mask that suctions exhaled air at the nares before it can be
diluted. A downside is that this can cause problems with the
mask seal. Another option is to record is the TcPCO2. These
surrogate measures of PCO2 are useful only if calibrated and
validated (ideally with an arterial or capillary blood gas).22,99
As mentioned in Chapter 8, a PETCO2 tracing should show a
plateau.
Titration Protocol
The recommended PAP titration protocol for adults and
children is shown in Tables 199 and 1910.62 CPAP is
usually started at 4 to 5 cm H2O and then increased for
obstructive apneas, hypopneas, RERAs, and snoring. Usually,
as pressure is increased, the apneas hypopneas RERAs
snoring resolve in that order.105 CPAP is increased in
adults after two obstructive apneas, three hypopneas, or five
RERAs and no more often than every 5 minutes. When
titrating BPAP, starting pressures of 8/4 cm H2O are typically
used. Both IPAP and EPAP are increased together for
obstructive apnea. For obstructive hypopneas, RERAs, and
snoring, the IPAP alone is increased. The clinical guidelines
suggest that the IPAP-EPAP difference should be at least 4
but not greater than 10 cm H2O. Note that, when NPPV
titration is discussed later, a wider IPAP-EPAP difference
can be used. In general, if the IPAP-EPAP difference widens,
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 Chapter 19 Positive Airway Pressure Treatment 331

Flow

Chest
8/4 cm H2O
Abdomen

Rate 18
Intercostal
EMG

Flow

Chest
15/5 cm H2O
Abdomen

Rate 12
Intercostal
EMG

FIGURE 1919 A patient with neuromuscular disease underwent an NPPV titration. When the level of pressure support was increased,
there was a decrease in the respiratory rate and in the intercostal electromyogram (EMG). From Berry RB: Initiating NPPV treatment with
patients with chronic hypoventilation. Sleep Med Clin 2010;5:485505.

TABLE 199
Continuous Positive Airway Pressure Titration Guidelines62
ADULTS AND CHILDREN > 12 YR CHILDREN < 12 YR
Beginning pressure (cm H2O; minimum) 4 4
Maximum pressure (cm H2O) 20 15
Increase CPAP in at least 1 cm H2O increments Increase pressure for: Increase pressure for:
no more frequently than every 5 min 2 obstructive apneas 1 obstructive apnea
3 hypopneas 1 hypopnea
5 RERAs 3 RERAs
3 min loud snoring 1 min loud snoring
Switch to BPAP Intolerant to CPAP
Events still present on CPAP of 15 cm H2O (option)
Snoring guidelines state that pressure may be increased.
BPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; RERAs = respiratory effortrelated arousals.

an increase in EPAP is often needed to maintain upper
airway patency. Higher PAP is needed for the supine posi-
tion and during REM sleep.106,107 For this reason, an effec-
tive pressure during supine REM sleep should be determined
if possible during the titration.62 Note that the recommended
maximum CPAP and number of events triggering pressure
changes are lower in children.
If the patient awakens and complains of excessive pres-
sure, pressure should be lowered. If this does not work, a
switch from CPAP to BPAP or use of flexible PAP may be
tried. When switching from CPAP to BPAP, one approach is
to use IPAP 2 cm H2O higher than CPAP and EPAP 2 cm
H2O lower. Thus, with a change from CPAP of 16, one would
use BPAP 18/14 cm H2O. Another approach is to use EPAP
= CPAP, and IPAP = EPAP + 4 cm H2O and titrate pressure
upward if needed. Of note, in pressure-intolerant patients,
sleep in the lateral position or with the head elevated can be
tried to reduce the required level of pressure.108 If mouth leak
is a problem, a chin strap can be tried followed by an orona-
sal mask. In patients with allergic rhinitis or nasal conges-
tion, use of HH from the start of the study is suggested.
Although studies have not shown a benefit from using pro-
phylactic HH in all patients, many sleep centers find it to
be very useful. Once the nose is congested, this problem is
not easily reversed. If there is excessive mask leak, a readjust-
ment of the mask, change in mask size, or change in mask
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332 Chapter 19 Positive Airway Pressure Treatment
TABLE 1910
Bilevel Positive Airway Pressure Titration Guidelines62
Beginning pressure (cm H2O)
IPAP/EPAP
Maximum IPAP (cm H2O)
Minimum PS (cm H2O)
Maximum PS (cm H2O)
Increase BOTH IPAP AND EPAP in at least 1 cm H2O
increments no more frequently than every 5 min
Increase IPAP in at least 1 cm H2O increments no
more frequently than every 5 min
Snoring guidelines state that pressure may be increased.
EPAP = expiratory positive airway pressure; IPAP = inspiratory positive airway pressure; PS = pressure support = IPAP EPAP; RERAs = respiratory effortrelated
arousals.
type is indicated. Overtightening of the mask straps is
strongly discouraged. It is also worth mentioning that some
patients with severe upper airway narrowing may tolerate a
higher initial pressure (810 cm H2O) better than the usual
low starting pressure. This is also true of patients already
using CPAP at home. If the patient is not falling asleep on
PAP, he or she should be asked what is bothering him or her.
PAP and Supplemental Oxygen
The addition of supplemental oxygen during PAP titration is
sometimes needed62 (Table 1911). Some patients will exhibit
significant arterial oxygen desaturation despite adequate
airflow, especially during REM sleep. Persistent hypoxemia
in these conditions may be due to hypoventilation or
ventilation-perfusion mismatch (often due to chronic lung
disease). In some studies of titration in patients with OHS,
a substantial number of patients required the addition of
supplemental oxygen. If the awake supine patient has an
SaO2 of 88% or lower or is already on supplemental oxygen
to maintain an acceptable awake SaO2, the addition of sup-
plemental oxygen will definitely be needed. Recall that even
in normal subjects, the arterial partial pressure of oxygen
(PaO2) falls on the order of 5 to 10 mm Hg during sleep.
Before adding supplemental oxygen, one can attempt to
adjust the PAP pressure settings to prevent the need for this
additional treatment. If the patient is requiring high oxygen
flows, optimizing PAP may allow reduction in the required
oxygen flow rate. First, an increase in CPAP can be tried to
eliminate unrecognized high upper airway resistance. If this
is not successful or not tolerated, CPAP can be changed to
BPAP (Fig. 1920). If the patient is already on BPAP, the level
of PS can be increased. If these interventions do not increase
the SaO2 to an acceptable level or if higher pressure is not
tolerated, supplemental oxygen can be added to PAP. One
can start at 1 L/min flow and titrate up every 10 to 15 minutes
ADULTS CHILDREN < 12 YR
8/4 8/4
30 20
4 4
10 10
Increase pressure for: Increase pressure for:
2 obstructive apneas 1 obstructive apnea
Increase pressure for: Increase pressure for:
3 hypopneas 1 hypopnea
5 RERAs 3 RERAs
3 min loud snoring 1 min loud snoring
TABLE 1911
Addition of Supplemental Oxygen during Positive
Airway Pressure Titration
Addition of supplemental oxygen
Awake supine SaO2 while breathing room air 88%.
During PAP titration when SaO2 88% for 5 min in the
absence of obstructive respiratory events.
Goal of addition of supplemental oxygen SaO2 between
88% and 94%.
Minimum starting rate of oxygen is 1 L/min.
O2 rate increased by 1 L/min with an interval no shorter
than 15 min until SaO2 is between 88% and 94%.
Attach supplemental oxygen at PAP device outlet.
Weaning down of oxygen flow may be attempted by
change from CPAP to BPAP or increased in IPAP if already
on BPAP.
BPAP = bilevel positive airway pressure; CPAP = continuous positive airway
pressure; IPAP = inspiratory positive airway pressure; PAP = positive airway
pressure; SaO2 = arterial oxygen saturation.
Adapted from Kushida CA, Chediak A, Berry RB, et al: Positive Airway Pressure
Titration Task Force, American Academy of Sleep Medicine: Clinical guidelines
for the manual titration of positive airway pressure in patients with
obstructive sleep apnea. J Clin Sleep Med 2008;4:157171.
with a goal of attaining an acceptable SaO2 (8894%). Most
clinicians would use a target 92% to 94% to allow for vari-
ability and a margin of safety.
It is important to recognize that the effective oxygen con-
centration will depend on both the supplemental oxygen
flow (L/min) and the machine flow109,110 (Fig. 1921).
Increases in machine flow associated with higher pressure or
mask/mouth leak can dilute a given flow of supplemental
oxygen. For example, if a patient with chronic lung disease
requires supplemental oxygen at 2 L/min to maintain an
SaO2 of 94% while awake without CPAP, on CPAP the
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 Chapter 19 Positive Airway Pressure Treatment 333

CPAP  15 cm H2O BPAP 18/11 cm H 2O

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin EMG

PAP
flow

Chest

Abdomen

SpO2 94%
81%

FIGURE 1920 A patient on continuous positive airway pressure (CPAP) of 15 cm H2O has persistent arterial oxygen desaturation without discrete events. The
options are to add supplemental oxygen, try an increase in CPAP, or switch to bilevel positive airway pressure (BPAP). A switch to BPAP was effective in this patient.
EMG = electromyogram; PAP = positive airway pressure; SpO2 = pulse oximetry.

50
4 Lpm backup rate when obstructive events have disappeared.
45 Patient with CompSA have predominantly obstructive or
40 mixed apneas during the diagnostic sleep study (or diagnos-
FIO2 (%)

35
2 Lpm tic portion of a split study) occurring at 5/hr or greater. The
30
CMS definition of CompSA requires that greater than 50%
of the residual respiratory events on PAP are central apneas
25 0 Lpm or central hypopneas, the central AHI is 5/hr or greater, and
20
the total AHI is 5 or greater (Appendix 19-3). Patients with
15 a combination of OSA and CSB may manifest CSB-central
0 4 12 20
CPAP (cm H2O) apneas when CPAP eliminates obstructive events. These
patients meet the definition of CompSA. Other patients
FIGURE 1921 Approximate change in effective fractional concentration of oxygen in taking potent opiates develop central apneas on CPAP (treat-
inspired gas (FiO2) with supplemental oxygen and various continuous positive airway ment emergent central apneas) or central apneas persist
pressure (CPAP) levels in a model system. Plotted from data from Yoder EA, Klann K, on CPAP. Other patients may manifest CompSA without
Strohl KP: Inspired oxygen concentrations during positive pressure therapy. Sleep Breath
an obvious cause (idiopathic CompSA). The treatment of
2004;8:15.
CompSA is discussed in detail in Chapter 21.
Patients with Cheyne-Stokes central apnea or idiopathic
CompSA tend to have high ventilatory drives or difficulty
required supplemental oxygen flow will likely be much maintaining sleep. Central apnea occurs because the PaCO2
higher (assuming the same fractional concentration of drops below the apneic threshold. The approach to CompSA
oxygen on CPAP treatment is still required). and PAP titration protocol for handling central apneas varies
between sleep centers.111113 One approach is to increase
CPAP only until the obstructive apneas and hypopneas are
Complex Sleep Apnea
eliminated. CPAP is increased further only if RERAs are
CompSA is defined as a form of central apnea specifically believed to be causing central apneas (after the arousals).
identified by the persistence or emergence of central apneas Many patients will stabilize if they enter stage N3 sleep
or hypopneas upon exposure to CPAP or a BPAP without a (i.e., patience rather than increasing the CPAP). A small
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334 Chapter 19 Positive Airway Pressure Treatment
reduction in pressure to one not associated with central
apneas can also be tried. Some patients will also improve in
the lateral sleeping position. Switching from CPAP to BPAP
without a backup rate is NOT indicated and may actually
contribute to ventilatory instability. Many patients with
CompSA when treated with CPAP on a chronic basis will
have a resolution of the central apneas.111,112 Others with CSB
or narcotics as a cause for ventilatory instability may con-
tinue to have frequent central events on chronic CPAP treat-
ment. These patients should undergo another PAP titration
with ASV or BPAP with a backup rate.113,114 Unless there are
financial constraints, it is better to utilize an entire night to
perform an ASV titration. As discussed in Chapter 21 some
patients with CompSA are more easily treated in REM than
NREM sleep.
ASV Titration Protocol
The protocol for ASV titration varies with the type of device
(Adapt SV vs. BiPAP AutoSV). For the Adapt SV, EPP = 4 cm
H2O, PSmax of 10 cm H2O or greater is recommended.
EPAP should be increased slowly to allow the unstable ven-
tilatory pattern to stabilize. For the BiPAP auto SV advanced,
recommended settings are EPAPmin = 4 cm H2O, EPAPmax
= 15 cm H2O, PSmin = 0 cm H2O, PSmax = 20 cm H2O, Max
pressure = 25 cm H2O, rate = auto. If it is known that CPAP
greater than 10 cm H2O is needed to prevent obstructive
apnea, EPAPmin of 6 to 8 cm H2O could be tried. For
pressure-intolerant patients or those with a component of
hypoventilation (narcotics), PSmin of 4 cm H2O could be
used. Of note, most insurance providers have definite criteria
for reimbursement for ASV or BPAP with a backup rate
(Appendix 193). Usually more than 50% of the events on
CPAP must be either central apneas or central hypopneas.
Although most sleep centers do not report central hypop-
neas, this may be one case in which it is necessary to meet
reimbursement guidelines. In the AASM scoring manual,
identifying hypopneas as central or obstructive was recom-
mended only if a quantitative measure of respiratory effort
was recorded (esophageal pressure, calibrated respiratory
inductance plethysmography [RIP] belts, or diaphragmatic/
intercostal EMG).99
Adequacy of PAP Titration
According to the AASM clinical guidelines for the titration
of CPAP and BPAP,62 an optimal titration is one that reduces
the AHI to less than 5/hr for at least 15 minutes and should
include supine REM sleep at the final pressure without
repeated arousals. A good titration results in an AHI < 10/hr
or at least a 50% reduction in the AHI if the baseline AHI is
less than 15/hr. A good titration should include supine REM
sleep at the selected pressure that is not continually inter-
rupted by arousals. An adequate titration is one that does not
reduce the AHI < 10/hr but does reduce the AHI by 75%
from baseline, or one in which criteria for optimal or good
titration is met with the exception that supine REM sleep did
TABLE 1912
Alternative Methods of Starting Positive
Airway Pressure
PSG titration CPAP treatment.
Autotitration CPAP treatment.
APAP treatment.
CPAP treatment with empirical pressure then adjustments
based on symptoms, oximetry, or machine-residual AHI.
AHI = apnea-hypopnea index; APAP = autoadjusting positive airway pressure;
CPAP = continuous positive airway pressure; PSG = polysomnography.
not occur at the selected pressure. An unacceptable titration
does not meet any of these criteria. If clinically indicated, a
repeat titration should be ordered. In optimal, good, and
acceptable titrations, the SaO2 should remain above 90% at
the treatment pressure selected for chronic use. If a titration
shows borderline oxygenation, it is then prudent to check
nocturnal oximetry while the patient uses PAP at home.
ALTERNATIVE METHODS OF STARTING
PAP TREATMENT
A number of options are available for starting PAP after a
diagnosis of OSA has been made without the use of a PSG
PAP titration.26,115120 These options are especially relevant if
the diagnosis of OSA is based on a portable monitoring (PM)
study. The titration alternatives can also be used for patients
who are unwilling or unable to have a standard PSG titration.
The alternatives are listed in Table 1912 and include treating
the patient with an APAP device (titration not needed), per-
forming autotitration at home for several days to a week (at
least 3 days optimum) with subsequent CPAP treatment
based on the results, and starting PAP treatment based on a
prediction equation with subsequent adjustment based on
symptoms, machine readings, and nocturnal oximetry.
Equations to predict the optimal CPAP level have been
developed (Equation 193).116 The prediction equation can
provide an empirical treatment level or a reasonable starting
point for a PAP titration. However, the optimal treatment
pressure may differ substantially from the predicted pres-
sure. In our experience the formula considerably underesti-
mates the required pressure, especially in men.
CPAP predicted = (0.16 BMI) + (0.13 NC)
+ (0.04 AHI) 5.12
Equation 193
where BMI = body mass index and NC = neck circumference
in centimeters.
Example: BMI = 30, NC = 16 inches (40.6 cm), AHI = 30/hr
CPAP pred = (0.166 30) + (0.13 40.6) + (0.04 30) 5.12
= 4.8 + 5.3 + 1.2 5.12 = 7 cm H2 O
Most PAP devices provide an estimate of the residual
AHI. Some devices also separate apneas into clear airway
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 Chapter 19 Positive Airway Pressure Treatment 335

apneas and obstructive apneas. Desia and coworkers121 TABLE 1913

recently compared the PAP device residual AHI with PSG Examples of Autoadjusting Positive Airway
and found that using a PAP AHI of 8/hr had a sensitivity and Pressure Titration
specificity of 0.94 and 0.90, respectively, for detecting a PSG
PATIENT 1 PATIENT 2 PATIENT 3
AHI greater than 10/hr.
Masa and coworkers115 compared three clinical pathways Min pressure 4 4 4
including standard PSG titration, autotitration for one night limit (cm H2O)
followed by CPAP treatment based on the results, and CPAP Max pressure 20 20 20
based on a prediction formula with subsequent adjustments limit (cm H2O)
based on symptoms. At the end of a 12-week period, all Days used 14/14 3/6 11/12
patients were studied on their current CPAP pressure. All
three methods resulted in equivalent CPAP adherence, Average use 6 hr 31 min 2 hr 2 min 5 hr 5 min
control of the AHI, and improvement in subjective sleepi- 90th percentile 11.8 9.5 12.0
ness. Of note, 23% of the eligible patients were excluded. pressure
Other studies comparing algorithms using alternative modes (cm H2O)
of initiating PAP treatment with PSG found similar Average pressure 9.2 8 8.0
results.117120 If a patient is diagnosed as having sleep apnea (cm H2O)
by PM, one of the three alternative methods or traditional
AHI 4.0 3 15
PSG titration is needed if PAP treatment is indicated. Using
PM followed by a PSG titration would seem to have little Large leak* 5 min 1 hr 12 min
advantage compared with a split PSG study (if available). *Large leak defined as leak > twice the average leak of interfaces at a given
However, sometimes the results of PM uncover an unex- pressure.
AHI = apnea-hypopnea index.
pected problem (central apneas, low baseline SaO2, or CSB).
If these are present, a PSG titration is definitely indicated.

either the 95th percentile pressure or the 90th percentile

Patient Selection for Alternative Titrations
Patients with a number of conditions are not suitable for
APAP titration or treatment.2325,115 These include patients
who require or are likely to require supplemental oxygen
(low baseline SaO2), patients with hypoventilation, patients
likely to have central apneas (narcotics, congestive heart
failure), and patients who may require very high pressures.
Patients with severe pressure intolerance or moderate to
severe COPD who may require BPAP should also undergo a
PSG titration if possible.
Technique of Autotitration
The patient is educated about OSA and PAP treatment and
has mask fitting and instructions on use of an APAP device.
It is often useful for the patient to take a brief practice nap
during which she or he applies the interface, activates the
APAP device, and naps for about 15 or 20 minutes.115,119
This allows identification of interface problems and allows
for adjustment or change of interface. The patient then sleeps
on the APAP device at home for several nights. Usually, the
pressure limits of the device are set from 4 to 20 cm H2O.
In large patients likely to require high CPAP, starting with
pressure of 4 cm H2O may be uncomfortable, so a higher
low-pressure limit is chosen (810 cm H2O). For the
pressure-intolerant patient, a lower upper limit of pressure
can be chosen. A telephone hotline is available for interven-
tions similar to PAP treatment. The device is then returned
and the information transferred to a computer. The quality
of the autotitration can be noted including amount of use
(adherence), residual AHI, and amount of leak. Typically,
pressure (depending on device) is chosen for chronic PAP
treatment. If the APAP titration is suboptimal owing to poor
adherence, high leak, or high residual AHI, another attempt
can be made using a different mask, HH, or other interven-
tions. If two attempts at an APAP titration are unsuccessful,
the patient can be referred for a PSG titration. Table 1913
shows three examples of typical APAP titrations. Patient 1 is
ideal with good adherence, low leak, a 90th percentile pres-
sure well within pressure limits, and a good residual AHI.
Based on this study, CPAP of 12 cm H2O could be used for
chronic treatment. Patient 2 is an example of a poor titration.
There is poor adherence and very high leak. The patient
complained of being dry despite using a high humidity
setting. The patient could be changed from a nasal to a full
face mask and the study repeated. Patient 3 shows good
adherence but the residual AHI is very high. The apnea index
was 13/hr and the hypopnea index 2/hr. The patient was
taking methadone. The high residual AHI was believed to be
due to central apneas. The patient was referred for a PSG PAP
titration. In retrospect, the patient was not a good candidate
for an APAP titration.
Follow-up of Patients on PAP Treatment
Because the pattern of adherence is set early, obtaining a
download within the first week and having a face-to-face
visit at or soon after 4 weeks of use is recommended. As
noted previously, CMS rules require at least 1 month of 70%
of nights with greater than 4 hours of use. This month of
adherence must occur within the first 3 months of CPAP use
for treatment to continue to be reimbursed. In addition to
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336 Chapter 19 Positive Airway Pressure Treatment

Pressure (cm H2O) CPAP pressure

20 CPAP
12.0
15
10
5
0
0 1 2 3 4 5 6 7 8 Indices
Sleep therapy flags 6.9% of night in PB

PB CA 1.5
CA OA 1.9
OA H 2.4
H FL 0.0
FL
VS VS 102.9
RE RE 2.8
AHI 5.8
0 1 2 3 4 5 6 7 8
Min in large leak
Total leak (LPM) Normal mask fit Large leak Total leak
0.0 min
% of night in
100
Large leak
50 0%
Average leak 43.0
0 1 2 3 4 5 6 7 8

FIGURE 1922 Sample PAP device download on a patient using continuous positive airway pressure (CPAP) of 12 cm H2O. The
residual apnea-hypopnea index (AHI) is 5.8 (adequate) but snoring is very prominent in the second half of the night. Leak is not
increased. On the basis of this information CPAP was increased to 13 cm H2O. Large leak is defined as a leak greater than twice the
intentional leak from interfaces at that pressure. CA = clear airway apnea; FL = flow limitation; H = hypopnea; OA = obstructive airway
apnea; PB = periodic breathing; RE = respiratory effortrelated arousal; VS = vibratory snore.

the adherence data, most PAP machines give information on
leak and residual AHI. Some can give detailed information
about residual events including clear airway events (central
apneas). Three studies found a surprisingly high proportion
of patients well treated with CPAP who had elevated AHI
values on their current treatment pressures.122124 A high
residual AHI found on CPAP machine download would
suggest that the current pressure was inadequate (unless the
events were central apneas) or that an inadequate mask seal
significantly reduced the delivered pressure. Some CPAP and
APAP devices present the residual AHI, AHI, hypopnea
index (HI), and a snoring index. If the residual apnea index
exceeds the HI, this is a clue that central apnea may be
present. Recall that as pressure increased, first obstructive
apnea then hypopnea resolve. However, false elevations of
the AHI can occur. Recently, CPAP and APAP devices can
separate apneas into obstructive apneas and clear airway
apneas. In Figure 1922, a sample report from a patient on
CPAP shows a reasonable residual AHI and no evidence of
excessive leak. However, there is evidence of considerable
snoring and slightly higher pressure is indicated. A high
residual AHI in a patient with congestive heart failure or
potent narcotic use would suggest the possibility of central
apneas. High leak would suggest need for better interface fit.
The interface could be adjusted or changed to a different size
or interface type. We have found it very useful to pressurize
the mask in the office before the patient leaves to check the
seal. If extreme dryness is present and a reasonable humidity
setting has been used, the function of the humidifier should
be checked, the possibility of mouth leak considered (if the
patient has a nasal mask), or the fit of the mask should be
evaluated. If a mouth leak is suspected, one could try a full
face mask or chin strap. The patients bed partner often pro-
vides important clues as to persistent snoring or apnea,
pulling the mask off during the night, noisy mask, or mouth
leak. Most clinicians have the patient fill out an Epworth
Sleepiness Scale each visit; this is used along with questions
about the quality of sleep to assess effectiveness of CPAP
treatment. In patients with significant insomnia, use of a
hypnotic could be considered once sleep hygiene and medi-
cation side effects are optimized.
NPPV Titration and Treatment
The titration of NPPV focuses on providing ventilatory
support in addition to maintaining an open airway.22,124
Patients with neuromuscular disorders, thoracic cage disor-
ders, or disorders of inadequate ventilatory control may not
be obese and may not require as high an EPAP as patients
with OSA or OHS.22,125,126 IPAP and EPAP are titrated as per
the protocol discussed previously to eliminate obstructive
events. However, the goal is to provide adequate PS without
using excessive pressure. Therefore, BPAP of 16/4 or 20/5 cm
H2O might be typical pressures. The ST mode is used for
treatment of all patients with central ventilatory control
disorders and is also recommended for patients with
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neuromuscular disorders and thoracic cage disorders. These
patients may not reliably cycle the BPAP device from EPAP
to IPAP. The ST mode is also needed if central apneas are
noted during the NPPV titration. The backup rate is usually
set 1 to 2 breaths below the sleeping spontaneous breathing
rate (810 breaths/min minimum). The cycle time in seconds
is equal to 60 divided by the respiratory rate in breaths per
minute. The Ti is chosen between 30% and 40% of the cycle
time. When expressed as a fraction of the cycle time, this is
also known as the %IPAP time.
Example: If the respiratory rate = 15,
cycle time = 60/15 = 4 sec.
If the %IPAP time is 30%, the Ti would be 1.2 sec.
In general, patients with airflow obstruction (COPD) are
best treated with 30% %IPAP time and those with restrictive
disorders may do better with 40% %IPAP time. One manu-
facturer recommends using 1.5 seconds as the default inspi-
ratory time for BPAP-ST. The rise time is the time from start
of the IPAP cycle until IPAP pressure is reached. It is typi-
cally around 200 msec (200600 msec) but can be varied for
patient comfort.
Goals of NPPV Titration and Treatment
The goals of the NPPV treatment vary between patients22,125,126
but generally include (1) improving sleep quality and pre-
venting nocturnal dyspnea, (2) preventing nocturnal
hypoventilation (or worsening of hypoventilation during
sleep if daytime hypoventilation is present), and (3) provid-
ing respiratory muscle rest. For patients with daytime
hypoventilation, use of NPPV can improve the quality of
life and delay or prevent the progression of respiratory
failure.125,126 The indications for NPPV127 are discussed in
TABLE 1914
Recommendations for Adjustment of Pressure Support during Noninvasive Positive Pressure
Ventilation Titration
PRESSURE CHANGE TRIGGER
IPAP/EPAP increased Eliminate apnea, hypopnea RERA
(see Table 1910)
PS increased 12 cm H2O Low tidal volume (<68 cc/kg IBW)
PS increased 12 cm H2O PaCO2 > 10 mm Hg above goal
PS increased 12 cm H2O Respiratory muscle rest not
achieved
PS increased 12 cm H2O SaO2 < 90% with tidal volume < 5 min
8 cc/kg (assumes discrete apnea,
hypopnea, RERAs not present)
EMG = electromyogram; EPAP = expiratory positive airway pressure; IBW = ideal body weight; IPAP = inspiratory positive airway pressure; PaCO2 = arterial carbon
dioxide pressure; PS = pressure support; RERA = respiratory effortrelated arousal; SaO2 = arterial oxygen saturation.
Chapter 19 Positive Airway Pressure Treatment 337
Chapter 21. The nocturnal PaCO2 goal is a value equal to or
less than the daytime PaCO2. However, sufficient PS may not
be tolerated initially. NPPV can be started on an outpatient
basis at low pressure (BPAP 8/4) and increased as tolerated
based on patient symptoms and oximetry, daytime PETCO2
measurements, or daytime arterial blood gas measure-
ments.128 However, an NPPV PSG titration is recommended
and allows a treatment to be chosen (IPAP, EPAP, backup
rate) that will eliminate obstructive apnea/hypopnea and
deliver optimal PS. Some patients will also require the addi-
tion of supplemental oxygen. Close follow-up is needed
because the given level of pressure support may prove inad-
equate if respiratory muscles weaken.
Titration using VT-BPAP is performed to determine an
effective EPAP. The ST mode is commonly used. The device
will automatically adjust PS to provide a desired tidal volume.
If pressure intolerance is a problem, a lower tidal volume
target with a higher respiratory rate (spontaneous or
machine-triggered) may be better tolerated.
NPPV Titration Protocol
Before the titration, the patient should be educated about
the process and be able to try different interfaces with
low pressure. Monitoring during a NPPV titration uses
methods similar to those for a PAP titration.22,125 A BPAP
device with capability to function in the ST or T mode is
needed. Most NPPV devices provide an analog output of
tidal volume that can be recorded. As shown in Figure 193,
monitoring and recording tidal volume in addition to flow
is useful because tidal volume depends on both flow and
Ti. A Best Clinical Practices NPPV titration protocol has
recently been published by the AASM and is a useful guide
to NPPV titration.22 Some of the titration recommendations
are listed in Table 1914. Generally, a starting pressure
DURATION
BETWEEN CHANGES GOAL
5 min Prevent apnea, hypopnea, RERAs,
snoring.
5 min Adequate tidal volume.
10 min Adequate ventilation and PaCO2
10 min Adequate respiratory muscle rest.
Reduction of respiratory rate with
higher tidal volumes and/or reduction
in inspiratory respiratory EMG activity.
Adequate oxygenation.
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338 Chapter 19 Positive Airway Pressure Treatment

BPAP of 8/4 cm H2O is used. The IPAP and EPAP are both Apnea-hypopnea index Hypopnea index (HI)
increased if obstructive apneas are noted. IPAP is increased (AHI)
for obstructive hypopneas. Otherwise, the IPAP is adjusted Adherence (all nights) 7.5/hr
to deliver adequate PS. The adequacy of PS can be assessed AHI 4.0/hr Apnea index 0.5/hr
by monitoring the delivered tidal volume (goal 68 mL/kg HI 3.5/hr
ideal body weight) and the SaO2. If the sleep center has the
Large leak 10 min
ability to monitor PETCO2 or TcPCO2, these measurements
can help guide the titration (if devices are calibrated and Average tidal volume 400 mL
validated). Monitoring of PETCO2 requires using a nasal Average rate 20
cannula under the mask to avoid dilution of the sampled Patient-triggered breaths 99%
gas. If there is continued arterial oxygen desaturation, PS A. Continue present treatment.
can be increased to reach a slightly higher tidal volume B. BPAP 12/4 cm H2O.
goal. If further increases in ventilation are desired but the
C. BPAP 10/6 cm H2O.
patient does not tolerate high PS, use of a higher backup
rate can be tried. D. Increase backup rate to 18 breaths/min.
As PS is increased, the finding of a higher tidal
volume and lower respiratory rate is compatible with a 3. Which of the following is most likely to be an effective
level of support providing respiratory muscle rest. However, treatment for a patient with the OHS (BMI = 40 kg/m2),
use of surface EMG recordings of respiratory muscle activ- neck circumference (NC) of 19 inches, and daytime PCO2
ity can also be useful. A reduction in respiratory muscle of 60 mm Hg?
EMG activity as PS increases would be evidence that a A. BPAP 19/16 cm H2O.
level of support was providing muscle rest. Supplemental B. BPAP 22/14 cm H2O.
oxygen can be added if desaturation persists despite opti- C. BPAP 16/8 cm H2O.
mization of NPPV. The same considerations for supple- D. BPAP 16/6 cm H2O.
mental oxygen apply as for CPAP/BPAP titrations for sleep
apnea.
4. A patient treated with CPAP of 12 cm H2O complains of
severe bloating. Pressure is reduced to 10 cm H2O but
bloating continues and the patients wife notes mild
Reimbursement for NPPV Devices snoring. What do you recommend?
NPPV devices are called RADs (respiratory-assist devices) A. CPAP 8 cm H2O.
and these are of two types: E0470 (BPAP) and E0471 (BPAP- B. APAP range 416 cm H2O.
ST). RADs have specific criteria for reimbursement depend- C. BPAP 12/8 cm H2O.
ing on the type of patient (see Appendix 193). The different
D. BPAP 10/6 cm H2O.
categories include neuromuscular disease/chest wall disor-
ders, hypoventilation, central apnea/CompSA, and COPD. A
5. A patient with severe COPD requiring supplemental
summary of the major CMS criteria is listed in Appendix
oxygen at 2 L/min during the day is found to have severe
193. The criteria may vary with the local carrier determina-
OSA with an AHI of 40/hr. BPAP of 16/12 cm H2O is the
tion and/or private health providers.
optimal treatment pressure. The patient is started on the
combination of BPAP and oxygen. Which of the follow-
ing is likely true about the required oxygen flow on BPAP
CLINICAL REVIEW QUESTIONS treatment?
1. Which of the following is most predictive of good PAP A. 2.5 L/min should be adequate.
adherence? B. Higher BPAP would require higher supplemental
A. Epworth Sleepiness Scale 16. oxygen flow.
B. Treatment prescription CPAP = 8 cm H2O vs. 16 cm C. The required supplemental oxygen flow would
H2O. increase with high mouth leak.
C. Spouse referral. D. A and B.
D. Entire night for PAP titration. E. B and C.

2. A patient with amyotrophic lateral sclerosis (ALS) who
weighs 70 kg is started on empirical BPAP-ST with pres-
sure of 8/4 cm H2O and a backup rate of 12 breaths/min.
The patient reports improved sleep and his wife notes no
snoring. On the basis of the following 6-week download
what do you recommend?
6. A patient with OSA undergoes an attended PAP titra-
tion. The CPAP treatment table follows. What pressure
do you recommend? (CA = central apnea; H = hypo-
pnea; MA = mixed apnea; OA = obstructive apnea;
TST = total sleep time). Assume all sleep is in the supine
position.
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REM AHI
CPAP TST SLEEP AHI REM OA MA CA H
7 30 0 20 0 10 0 0 0
8 30 10 10 30 0 0 0 5
9 30 20 4 6 0 0 0 2
10 30 10 10 0 0 0 5 0
11 30 10 20 0 0 0 10 0
A. 7.
B. 8.
C. 9.
D. 10.
E. 11.
Answers
1. A. Patients with daytime sleepiness are more likely to
experience a symptomatic benefit and adhere to PAP
treatment. The level of pressure does not seem to be a
factor in unselected patients. Individual patients may
benefit from interventions such as BPAP, APAP, autoB-
PAP, or flexible PAP. Use of a split-night study versus an
entire night of titration does not seem to be a major factor
in most studies.
2. B. The tidal volume is low and respiratory rate high. For
a 70-kg individual, the ideal tidal volume is around 500
to 600 mL (68 mL/kg). An increase in PS is indicated.
Because the AHI is low, there is no need to increase the
EPAP. If tidal volume increases, one would expect the
respiratory rate to decrease (e.g., 2015 breaths/min). At
this point, there is no indication to use a higher respira-
tory rate.
3. B. In patients with OSA or OHS and a large neck circum-
ference, a relatively high CPAP or EPAP is needed to
prevent obstructive apnea. BPAP with a PS of 4 cm H2O
might be used in a patient with OSA and pressure intoler-
ance to keep the upper airway open. Some patients with
OHS who will respond to CPAP alone experience a
reduction in daytime PCO2 with chronic treatment.
However, given the significant hypercapnia, a higher PS
(if tolerated) is indicated. EPAP of 8 would be unlikely to
prevent obstructive apnea (at least during supine REM
sleep). If the patient did not tolerate BPAP of 22/14, one
could try 20/14 cm H2O.
4. C. One could argue that any of the answers might
be reasonable. However, patients with bloating often
require a change to BPAP. A BPAP of 12/8 should provide
similar treatment to CPAP of 10. At this level, there was
only mild snoring. If bloating persists, one could try
lower pressure. CPAP of 8 cm H2O would also likely
provide relief from bloating but would likely result in an
increased AHI. In some situations, this might be accept-
able. On APAP, the mean pressure is often 2 to 6 cm
H2O below the 90th percentile pressure (commonly
selected for CPAP). In most individuals, the difference is
Chapter 19 Positive Airway Pressure Treatment 339
in the 2 cm H2O range. This may not provide enough
pressure reduction but would not be an unreasonable
approach.
5. E. The patient likely requires fairly high BPAP and,
therefore, 2.5 L/min will likely not be adequate given
that 2 L/min provides a daytime SaO2 of only 94%. The
required supplemental oxygen flow increases with
increasing levels of PAP due to the higher delivered flow
rate. The supplemental oxygen flow can be adjusted
during a PSG PAP titration. However, checking nocturnal
oximetry on treatment is suggested to determine oxygen
requirements in the home setting.
6. C. On CPAP of 9 cm H2O, the AHI = 4/hr and supine
REM sleep was recorded. Higher pressure was associated
with central apneas.
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Practice Parameters for APAP and CPAP/BPAP
(Selected Recommendations)
CPAP/BPAP Recommendations*
4.1.1 Treatment with CPAP must be based on a prior diag-
nosis of OSA established using an acceptable method.
(Standard)
4.1.2 CPAP is indicated for the treatment of moderate to
severe OSA. (Standard)
4.1.3 CPAP is recommended for the treatment of mild
OSA. (Option)
4.1.4 CPAP is indicated for improving self-reported sleep-
iness in patients with OSA. (Standard)
4.1.5 CPAP is recommended for improving quality of life
in patients with OSA. (Option)
4.2.1 Full-night, attended polysomnography performed
in the laboratory is the preferred approach for titration to
determine optimal PAP; however, split-night, diagnostic-
titration studies are usually adequate. (Guideline)
4.3.1 CPAP usage should be objectively monitored to help
ensure utilization. (Standard)
4.3.2 Close follow-up for PAP usage and problems in
patients with OSA by appropriately trained health care pro-
viders is indicated to establish effective utilization patterns
and remediate problems, if needed. This is especially impor-
tant during the first few weeks of PAP use. (Standard)
4.3.3 The addition of heated humidification is indicated
to improve CPAP utilization. (Standard)
4.3.4 The addition of a systematic educational program is
indicated to improve PAP utilization. (Standard)
4.4.1 After initial CPAP setup, long-term follow-up for
CPAP-treated patients with OSA by appropriately trained
health care providers is indicated yearly and as needed to
troubleshoot PAP mask, machine, or usage problems.
(Option)
4.4.2 CPAP and BPAP therapy are safe; side effects
and adverse events are mainly minor and reversible.
(Standard)
4.5.1 While the literature mainly supports CPAP therapy,
BPAP is an optional therapy in some cases in which high
*From Kushida CA, Littner MR, Hirshkowitz M, et al: Practice
parameters for the use of continuous and bilevel positive airway pressure
devices to treat adult patients with sleep related breathing disorders. Sleep
2006;29:375380.
Appendix 19-1
pressure is needed and the patient experiences difficulty
exhaling against a fixed pressure or coexisting central
hypoventilation is present. (Guideline)
4.5.2 BPAP may be useful in treating some forms of
restrictive lung disease or hypoventilation syndromes associ-
ated with daytime hypercapnia. (Option)
APAP Recommendations
3.1. APAP is not recommended to diagnose OSA.
(Standard)
3.2. Patients with CHF, significant lung disease such as
COPD, patients expected to have nocturnal arterial oxyhe-
moglobin desaturation due to conditions other than OSA
(e.g., obesity hypoventilation syndrome), patients who do
not snore (either naturally or as a result of palate surgery),
and patients who have central sleep apnea syndromes are not
currently candidates for APAP titration or treatment.
(Standard)
3.3. APAP devices are not currently recommended for
split-night titration. (Standard)
3.4. Certain APAP devices may be used during attended
titration with polysomnography to identify a single pressure
for use with standard CPAP for treatment of moderate to
severe OSA. (Guideline)
3.5. Certain APAP devices may be initiated and used in
the self-adjusting mode for unattended treatment of patients
with moderate to severe OSA without significant
co-morbidities (CHF, COPD, central sleep apnea syndromes,
or hypoventilation syndromes). (Option)
3.6. Certain APAP devices may be used in an unattended
way to determine a fixed CPAP treatment pressure for
patients with moderate to severe OSA without significant
co-morbidities (CHF, COPD, central sleep apnea syndromes,
or hypoventilation syndromes). (Option)
From Morgenthaler TI, Aurora RN, Brown T, et al: Standards of Practice
Committee of the AASM: Practice parameters for the use of autotitrating
continuous positive airway pressure devices for titrating pressures and
treating adult patients with obstructive sleep apnea syndrome: an update
DaneshGroup.com
for 2007. Sleep 2008;31:141147.
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344 Chapter 19 Positive Airway Pressure Treatment

3.7. Patients being treated with fixed CPAP on the basis
of APAP titration or being treated with APAP must have
close clinical follow-up to determine treatment effectiveness
and safety. This is especially important during the first few
weeks of PAP use. (Standard)
3.8. A re-evaluation and, if necessary, a standard attended
CPAP titration should be performed if symptoms do not
resolve or if the APAP treatment otherwise appears to lack
efficacy. (Standard)

APAP = autotitrating positive airway pressure; BPAP = bilevel positive airway pressure; CHF = congestive heart failure; COPD = chronic obstructive
DaneshGroup.com
airway pressure; CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea; PAP = positive airway pressure.

The details of local carrier determinations can vary by region
and are frequently updated.
Excerpts from the Local Carrier Determination (LCD) for
Positive Airway Pressure (PAP) devices for the treatment of
Obstructive Sleep Apnea (L11518) CIGNA-DMAC.
Initial Coverage
A single level continuous positive airway pressure (CPAP)
device (E0601) is covered for the treatment of obstructive
sleep apnea (OSA) if criteria AC are met:
A. The patient has a face-to-face clinical evaluation by the
treating physician prior to the sleep test to assess the
patient for OSA.
B. The patient has a Medicare-covered sleep test that meets
either of the following criteria (1 or 2):
1. The apnea-hypopnea index (AHI) or Respiratory Dis-
turbance Index (RDI)* is greater than or equal to 15
events per hour with a minimum of 30 events; or
2. The AHI or RDI is greater than or equal to 5 and less
than or equal to 14 events per hour with a minimum
of 10 events and documentation of:
a. Excessive daytime sleepiness, impaired cognition,
mood disorders, or insomnia; or
b. Hypertension, ischemic heart disease, or history of
stroke.
C. The patient and/or their caregiver have received instruc-
tion from the supplier of the CPAP device and accesso-
ries in the proper use and care of the equipment.
If a claim for a CPAP (E0601) is submitted and all of the
criteria above have not been met, it will be denied as not
medically necessary.
Sleep Tests
Coverage of a PAP device for the treatment of OSA is limited
to claims where the diagnosis of OSA is based upon a
Medicare-covered sleep test (Type I, II, III, IV, Other). A
Medicare-covered sleep test must be either a polysomno-
gram performed in a facility-based laboratory (Type I study)
or a home sleep test (HST) (Types II, III, IV, or Other). The
test must be ordered by the beneficiarys treating physician
and conducted by an entity that qualifies as a Medicare pro-
vider of sleep tests and is in compliance with all applicable
state regulatory requirements.
*Here RDI is used for Home Sleep Testing as # apneas + hypopneas/hr of
monitoring time; respiratory eventrelated arousals (RERAs) are not
included in either the AHI or the RDI.
Appendix 19-2
A Type I sleep test is the continuous and simultane-
ous monitoring and recording of various physiological
and pathophysiological parameters of sleep with physi-
cian review, interpretation, and report. It is facility-based
and must include sleep staging, which is defined to
include a 14 lead electroencephalogram (EEG), electro-
oculogram (EOG), submental electromyogram (EMG)
and electrocardiogram (ECG). It must also include at
least the following additional parameters of sleep: airflow,
respiratory effort, and oxygen saturation by oximetry. It
may be performed either as a whole night study for diag-
nosis only or as a split night study to diagnose and ini-
tially evaluate treatment.
An HST is performed unattended in the beneficiarys
home using a portable monitoring device. A portable moni-
toring device for conducting an HST must meet one of the
following criteria:
Type II deviceMonitors and records a minimum of
seven (7) channels: EEG, EOG, EMG, ECG/heart rate,
airflow, respiratory movement/effort and oxygen satu-
ration; or
Type III deviceMonitors and records a minimum
of four (4) channels: respiratory movement/effort,
airflow, ECG/heart rate and oxygen saturation; or
Type IV deviceMonitors and records a minimum of
three (3) channels, one of which is airflow that allows
direct calculation of an AHI or RDI; or
OtherDevices that monitor and record a minimum of
three (3) channels that include actigraphy, oximetry,
and peripheral arterial tone that allow calculation of
an AHI or RDI.
Continued Coverage beyond the First 3 Months
of Therapy
Continued coverage of a PAP device (E0470 or E0601)
beyond the first three months of therapy requires that no
sooner than the 31st day but no later than the 91st day after
initiating therapy, the treating physician must
1. Face-to-face a clinical re-evaluation by the treating
physician with documentation that the symptoms of
OSA have improved; and
2. Objective evidence of adherence to use of the PAP
device, reviewed by the treating physician
Adherence to therapy is defined as use of PAP 4 hours
per night on 70% of nights during a consecutive thirty (30)
day period anytime during the first three (3) months of
initial usage.
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346 Chapter 19 Positive Airway Pressure Treatment

If the above criteria are not met, continued coverage of a
PAP device and related accessories will be denied as not
medically necessary.
Beneficiaries who fail the initial 12-week trial are eligible
to re-qualify for a PAP device but must have both:
1. Face-to-face clinical re-evaluation by the treating phy-
sician to determine the etiology of the failure to
respond to PAP therapy; and
2. Repeat sleep test in a facility-based setting (Type 1
study).

Available at http://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?ContrNum=18003&ContrTypeId=10&LCDId=11518&ver=55&Date
=01%2f01%2f2011&DocID=L11518&bc=iAAAABAAQAAA&
DaneshGroup.com
 Appendix 19-3

Medicare Criteria for Reimbursement for

Respiratory-Assist Devices

Device terminology: E0470 = BPAP no backup rate; E0471 medical record should document relevant symptoms and
= BPAP with backup rate usage of the device up to that time. Failure of the patient to
be consistently using the device for an average of 4 hours per
24-hour period by the time of re-evaluation would represent
Requirements for Initial Coverage for 3 Months
noncompliant utilization for the intended purpose and
A. Restrictive thoracic and neuromuscular disorders (Table expectations of benefit. This would constitute reason for
1915) Medicare to deny continued coverage as not medically nec-
B. Hypoventilation syndrome (Table 1916) essary. A signed and dated statement by the treating physi-
C. Central apnea/CompSA (Table 1917) cian no sooner than 61 days after initiating device use,
D. Severe COPD (Table 1918) declaring that the patient is compliantly using the device (an
average of 4 hours per 24-hour period) and that the patient
is benefiting from its use, must be obtained by the supplier
Coverage beyond 3 Months
of the device before continued coverage beyond 3 months.
Coverage beyond 3 months requires a physician evaluation
no sooner than the 61st day after starting the RAD. The

TABLE 1915
Medicare Guidelines for Reimbursement for Respiratory Assist Device Restrictive Thoracic and
Neuromuscular Disorders
Criterion A: There is documentation in the patients medical record of a neuromuscular disease (ALS) or severe thoracic cage
abnormality
AND
Criterion B1: PaCO2 45 mmHg while awake and breathing patients prescribed FIO2.
AND Criterion B2 OR B3
Criterion B2: Sleep oximetry shows SaO2 88% for at least 5 min of nocturnal recording time while breathing prescribed FIO2
(2 hr minimum recording time).
OR
Criterion B3 (NMD only): Maximal inspiratory pressure < 60 cm H2O or FVC < 50% predicted.
AND
Criterion C: COPD does not contribute significantly to the patients pulmonary limitation.
Either E0470 or E0471 (backup rate) will be covered for first 3 mo of treatment.
ALS = amyotrophic lateral sclerosis; COPD = chronic obstructive pulmonary disease; FIO2 = fractional concentration of oxygen in inspired gas; FVC = forced vital
capacity; NMD = neuromuscular disease; PaCO2 = arterial partial pressure of carbon dioxide; SaO2 = arterial oxygen saturation.

BPAP = bilevel positive airway pressure; COPD = chronic obstructive pulmonary disease; CompSA = complex sleep apnea; RAD = respiratory-assist
device.
Available at http://www.cms.gov/mcd/viewlcd.asp?lcd_id=5023&lcd_version=56&show=all
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348 Chapter 19 Positive Airway Pressure Treatment

TABLE 1916
Medicare Guidelines for Reimbursement for Respiratory Assist Device Hypoventilation Syndrome
HYPOVENTILATION SYNDROME (E0470 DEVICE, BPAP WITHOUT A BACKUP RATE)
An E0470 will be covered for first 3 mo of treatment if Criteria A and B and either C or D is met.
Criterion A: Arterial blood gas PaCO2 45 mm Hg while awake and breathing patients prescribed FIO2.
AND
Criterion B: Spirometry shows an FEV1/FVC 70% and FEV1 50% of predicted.
AND either Criterion C or D
Criterion C: An arterial blood gas PaCO2, done during sleep or immediately on awakening, and breathing the patients
prescribed FIO2, show the beneficiarys PaCO2 worsened 7 mm Hg compared with original result in Criterion A.
Criterion D: A facility-based PSG demonstrates oxygen saturation < 88% for 5 min of nocturnal recording time (minimal
recording time of 2 hr) that is not caused by obstructive upper airway events.
HYPOVENTILATION SYNDROME (E0471 DEVICE, BPAP WITH A BACKUP RATE)
An E0471 will be covered for first 3 mo of treatment if criterion A and B and either C or D is met.
Criterion A: A covered E0470 device is being used
AND
Criterion B: Spirometry shows an FEV1/FVC 70% and FEV1 50% of predicted.
AND either Criterion C or D
Criterion C: An arterial blood gas PaCO2, done while awake, and breathing the patients prescribed FIO2, show the beneficiarys
PaCO2 worsened 7 mm Hg compared with the arterial blood gas result used to qualify the patient for the E0470 device.
Criterion D: A facility-based PSG demonstrates SaO2 < 88% for 5 min of nocturnal recording time (minimal recording time of
2 hr) that is not caused by obstructive upper airway events (AHI < 5/hr) while using an E0470 device.
AHI = apnea-hypopnea index; BPAP = bilevel positive airway pressure; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; PaCO2 = arterial
partial pressure of carbon dioxide; PSG = polysomnography; SaO2 = arterial oxygen saturation.

TABLE 1917
Medicare Guidelines for Reimbursement for Respiratory-Assist Device Central Apnea and Complex Sleep
Apnea (E0470 or E0471)
Before initiating therapy, a complete facility-based attended PSG must be performed documenting the following criteria:
Criterion A: Diagnosis of central sleep apnea or complex sleep apnea.
AND
Criterion B: Significant improvement of the sleep-associated hypoventilation with the use of E0470 or E0471 device on settings
that will be prescribed for initial use at home, while breathing the patients usual prescribed FIO2.
Central sleep apnea is defined as
1. AHI > 5/hr.
2. Central apnea/hypopnea > 50% of the total apneas and hypopneas.
3. Central apneas or hypopneas 5/hr.
4. Symptoms of excessive sleepiness or disturbed sleep.
Complex sleep apnea is a form of central apnea specifically identified by the persistence or emergence of central apneas or
hypopneas upon exposure to CPAP or an E0470 when obstructive events have disappeared. These patients have
predominantly obstructive or mixed apneas during the diagnostic sleep study occurring at 5/hr. With use of a CPAP or
E0470, they show a pattern of apneas and hypopneas that meet the definition of central sleep apnea described previously.
AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure; FIO2 = fractional concentration of oxygen in inspired gas; PSG = polysomnography.

TABLE 1918
Medicare Guidelines for Reimbursement for Respiratory-Assist Device Severe Chronic Obstructive
Pulmonary Disease (E0470*)
Criterion A: An arterial blood gas PaCO2 52 mm Hg, done while awake and breathing the patients prescribed FIO2.
AND
Criterion B: Sleep oximetry demonstrates oxygen saturations < 88% for at least 5 min nocturnal recording time, done while
breathing oxygen at 2 L/min or the patients prescribed FIO2 (whichever is higher), 2-hr minimum recording time.
AND
Criterion C: Before initiating therapy, OSA (and treatment with CPAP) has been considered and ruled out.
If all above criteria are met, an E0470 with be covered for the first 3 mo of therapy.
*E0470 = BPAP with no backup rate.
CPAP = continuous positive airway pressure; FIO2 = fractional concentration of oxygen in inspired gas; OSA = obstructive sleep apnea; PaCO2 = arterial partial pressure
of carbon dioxide. DaneshGroup.com

Oral Appliance and Surgical
Treatment for Obstructive
Sleep Apnea
Chapter Points
Before treatment of snoring with an OA, the presence
or absence of OSA should be determined. If OSA is
present, treatment plans may change based on
severity. In addition, the presence of OSA mandates
different follow-up.
Treatment with an OA is indicated for patients
with primary snoring (when patients do not
respond to weight loss or the side sleep
position).
Although not as efficacious as CPAP, OAs are indicated
for use in patients with mild to moderate OSA who
prefer OAs to CPAP, do not respond to CPAP, are not
appropriate candidates for CPAP, or fail treatment
attempts with CPAP or treatment with behavioral
measures such as weight loss or sleep position
change.
OAs are not indicated for initial treatment of severe
OSA. Positive airway pressure is the treatment
of choice for patients with severe OSA. Upper
airway surgery may also supersede use of OA in
patients for whom surgery is predicted to be highly
effective.
OA devices include MRAs and tongue retaining/
stabilizing devices. The effectiveness of MRAs is better
documented and, at least some studies suggest, better
tolerated by patients.
Adjustable custom-fitted MRAs are preferred over
monobloc (boil and bite appliances).
A qualified dentist should evaluate potential OA
treatment candidates for suitability of OA treatment
from the dental standpoint, supervise appliance
fitting and adjustment, and see patients for
long-term follow-up to determine whether adverse
changes in dentition have occurred due to OA
treatment.
Chapter 20
Follow-up sleep testing after optimal OA adjustment is
NOT indicated for treatment of primary snoring but is
indicated for treatment of all severities of OSA. Sleep
testing may include a PSG, an attended type 3 home
sleep test, or unattended type 3 home sleep test
(airflow, effort, saturation, pulse, or electrocardiogram).
Follow-up with the treating clinician is needed to
assess the patient for signs and symptoms of
worsening OSA. If worsening is suspected, repeat sleep
testing with the OA in place is indicated.
The presence and severity of OSA must be determined
before initiating any type of upper airway surgical
treatment for presumed snoring.
Before undergoing surgery, patients should be advised
of potential success rates and complications as well as
treatment alternatives.
Tracheostomy is the only surgery uniformly effective
for severe OSA, although some series suggest MMA
may be 45% to 85% effective depending on how
surgical success is defined.
MMA is indicated for initial treatment of severe OSA
in patients who cannot tolerate or are unwilling to
adhere to PAP therapy and in whom OAs have been
considered and found ineffective or undesirable.
UPPP does not reliably normalize the AHI in patients
with moderate to severe OSA. Patients with severe
OSA should be offered PAP treatment. Patients with
moderate OSA should initially be offered PAP therapy
or an OA.
A PSG is recommended before TNA in children to
determine whether OSA is present and to determine
the severity. A PSG after TNA is recommended for
patients with persistent symptoms of OSA. Many
clinicians recommended a post-treatment PSG in
children with moderate to severe OSA before TNA (AHI
510 or > 10/hr, respectively).
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350 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea

bite opening and mandibular advancement. The MRAs are

ORAL APPLIANCE TREATMENT FOR OSA
ORAL APPLIANCES
An oral appliance (OA) can be defined as a device inserted
into the mouth for treatment of snoring or obstructive sleep
apnea (OSA).15 There are two main types, the tongue retain-
ing (stabilizing) device (TRD/TSD)69 (Fig. 201) and the
mandibular repositioning appliances (MRAs) (Figs. 202 to
204). The TSD/TRDs hold the tongue in a forward position
by retaining the tongue in a suction bulb.69 The MRAs are
attached to the dental arches and provide variable degrees of
also called mandibular advancing devices (MADs) or man-
dibular repositioning devices (MRDs). MRAs can come in
monobloc (boil and bit) fixed configurations or custom-
fitted appliances that can be adjusted to change the amount
of mandibular protrusion (advancement).
Evaluation of the Patient
Each candidate for an OA should be examined by a qualified
dentist to determine whether an OA is feasible and safe from
a dental standpoint. The dental examination should focus on

FIGURE 201 Left, Tongue retaining device (TRD).

Right, Tongue stabilizing device (TSD). The TRD is
fabricated for each patient whereas the TSD comes in
three standard sizes (small, medium, and large).

FIGURE 202 A Herbst appliance. The side arms allow

adjustment of the amount of mandibular protrusion. From
Berry RB: Sleep Medicine Pearls. 2nd ed. Philadelphia: Hanley
& Belfus, 2003, p. 175.

Herbst appliance

FIGURE 203 The patient is shown with and without the

Herbst appliance. The appliance moves the chin noticeably
forward.

Before
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Herbst appliance
 Chapter 20
FIGURE 204 Versions of the Thornton anterior positioner (TAP) oral appliance, which consists of two separate arches connected
by an advancing mechanism. Left two panels, The adjustment apparatus extends outward from the maxillary arch. This is turned
to change the amount of protrusion of the mandible by moving the hook which pulls the bar forward. Right, TAP-3 appliance; key
is used to advance the mandibular arch.
A B
the temporomandibular joint (TMJ), evidence or history of
bruxism, quality of dental occlusion, the presence of signifi-
cant periodontal disease, overall dental health, and protru-
sive ability. Cephalometrics or dental radiographs may be
indicated.10 The patients occlusion type should be noted.
Three classes (types) of skeletal occlusions are illustrated in
Figure 205. One might expect that patients with mandibu-
lar deficiency (retrognathia) would benefit the most from an
OA but the amount of improvement is somewhat unpredict-
able. The location of airway occlusion during sleep might
also be expected to predict the response to OA treatment.
Patients with occlusion mainly in the retroglossal area rather
than the retropalatal area might be expected to improve the
most with a MRA. However, in one study, some patients with
upper airway occlusion mainly in the velopharynx also
improved with MRA treatment.11
Exclusions and Contraindications
Patients must have a minimal amount of healthy teeth for an
MRA. A minimum of 6 to 10 teeth in each arch is needed.1,5
However, treatment with dental implants can permit future
MRA treatment in patients with insufficient dentition at the
time of evaluation. Patients must be able to open the jaw
adequately for OA insertion and must have the ability to
voluntarily protrude the mandible. Moderate to severe TMJ
disease or inadequate protrusive ability are contraindica-
tions. Mild TMJ dysfunction may actually improve with the
Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea 351
FIGURE 205 Lateral cephalometric views of three
distinct skeletal occlusions. A, A skeletal class I occlusion.
There is nearly ideal and dental balance. B, A skeletal
class II malocclusion (overjet, or retrognathia). There is
mandibular deficiency. Note the everted lower lip and
distance between the upper and the lower incisors. C, A
skeletal class III occlusion with mandibular hyperplasia and
maxillary hypoplasia (or prognathia). The upper incisor is
behind the lower incisor. AC, From Conely RS: Orthodontic
considerations related to sleep disordered breathing. Sleep
Med Clin 2009;5:80.
C
jaw positioned anteriorly during sleep. Moderate to severe
bruxism is also a contraindication in most cases. Bruxism
during sleep can actually damage some types of OAs.
However, bruxism in some patients improves with adequate
treatment of OSA. An experienced dental practitioner should
evaluate patients with bruxism for suitability for an OA. A
history of bruxism may also alter the choice of the type of
OA used. Of note, edentulous patients can be treated with a
TRD/TSD.
Mechanism of Action of OAs
OAs are believed to work by increasing upper airway size.
TRDs/TSDs move the tongue forward. MRAs move the
tongue and mandible forward, increasing the posterior air-
space. By stabilizing the mandibular position, MRAs resist
the downward rotation of the mandible with sleep and the
accompanying retrusion of the mandible. They may also
tense palatal muscles. Some studies have found an increase
in upper airway muscle tone with an MRA in place.12 As
noted previously, patients with airway closure mainly in the
velopharynx may also respond to OA treatment. In agree-
ment with this finding, a study of the effect of an MRA on
upper airway size during wakefulness using fiberoptic endos-
copy found the most significant increase in airway size was
at the velopharynx.13 Another study of videofluoroscopy
during sleep found increases in both the retroglossal and the
retropalatal airway size during sleep with an MRA in place.14
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352 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
Effectiveness
A number of studies (some controlled) have demonstrated
that OA devices are effective in reducing the apnea-hypopnea
index (AHI) in mild, moderate, and severe OSA.1,2 However,
because OAs are less effective than continuous positive
airway pressure (CPAP) in reducing the AHI to less than
10/hr, CPAP is considered the treatment of choice for mod-
erate to severe OSA. American Academy of Sleep Medicine
(AASM) practice parameters2 state that OAs are indicated
for treatment of mild and moderate OSA as well as snoring.
The practice parameters also state that OAs can be used in
severe OSA, although generally considered a third-line treat-
ment after positive airway pressure (PAP) and surgery. A
summary of effectiveness in a systematic review of OAs pub-
lished in 2006 is listed in Table 201. Although results dif-
fered considerably between studies, OA treatment was found
to be successful in about 50% of patients with mild to moder-
ate OSA (using an AHI < 10/hr as the definition of success).1
Of note, some patients with severe OSA can have an impres-
sive reduction in the AHI, although rarely to a value less than
10/hr (Fig. 206).
Studies have also documented that OA treatment improves
both subjective and objective sleepiness. Using a controlled
TABLE 201
Range of Effectiveness of Oral Appliances*
MILD TO MODERATE OSA
OA success 5781%
*Success is defined as a reduction of the AHI to < 10/hr.
AHI = apnea-hypopnea index; OA = oral appliance; OSA = obstructive sleep
apnea.
From Ferguson KA, Cartwright R, Rogers R, et al: Oral appliances for snoring
and obstructive sleep apnea: a review. Sleep 2006;29:244262.
120
110
Apnea hypopnea index (events/hour)
100
90
80
70
60
50
40
30
20
10
0 0
Without
device
FIGURE 206 Effectiveness of oral appliances (OAs) in a wide range of obstructive sleep apnea (OSA) patients. Note that some
patients with severe OSA had dramatic falls in the apnea-hypopnea index (AHI) and improvement in the arterial oxygen saturation
(SaO2). From Henke KG, Fratnz DE, Kuna ST: An oral mandibular advancement device for obstructive sleep apnea. Am J Respir Crit Care
Med 2000;161:423.
cross-over design (OA without protrusion as control),
Gotsopoulos and coworkers15 found significant improve-
ment in the subjective sleepiness (Epworth Sleepiness
Scale decreased from 9 to 7) and objective sleepiness
as assessed by the multiple sleep latency test (mean sleep
latency increased from 9.1 to 10.3 min).
Factors Predicting Effectiveness
Four variables appear to contribute to the degree of effective-
ness of OA treatment of OSA.1,16,17 These include (1) the
severity of the OSA, (2) amount of protrusion by the MRA,
(3) the presence or absence of positional sleep apnea, and (4)
the body mass index (BMI).1 The degree of protrusion of the
mandible with MRAs varies typically from 6 to 10 mm or
from 50% to 75% of the maximum the patient can volun-
tarily protrude the mandible on request. One study using the
same OA with different protrusions found a reduced AHI
with greater protrusion.16 Positional OSA defined as a supine
AHI > 2 lateral AHI predicts that OA will be more effec-
tive1,17 (Fig. 207). OA treatment also is more effective in
mild to moderate OSA (better chance of treatment AHI
falling in acceptable range). They also appear to be more
effective in the less obese patient.
Devices
The TSD is manufactured in three prefabricated sizes (small,
SEVERE OSA medium, and large), whereas TRDs are custom-fitted to each
1461%
patient. The patient inserts the tongue into the device and
gently pumps the bulb to apply suction. Once the tongue is
inserted, the bulb is released and the tongue is held forward
by suction. One study found the TSD to significantly reduce
the AHI, although not quite as well as an MRA.9 In addition,
the TSD had a lower compliance rate and was more likely to
20
Time below 90% oxygen saturation (%)
15
10
5
With Without With
device device device
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 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea 353

100% FIGURE 207 Effectiveness of OAs on positional and

nonpositional obstructive sleep apnea (OSA). Positional OSA
P = .029 was defined as patients with an apnea-hypopnea index [AHI]
80% P = .024 P = .028 supine > 2 AHI nonsupine. A, Percentage of ALL positional
69.0% and nonpositional patients with a post-treatment AHI < 5/
64.9% 65.2%
hr. B, Considering only patients with a pretreatment AHI
60% 10/hr, the percentage of positional and nonpositional
patients with a post-treatment AHI < 5/hr. That is, AHI 10
43.3% to < 5/hr. C, Considering only patients with a pretreatment
40% AHI 10/hr, the percentage of positional and nonpositional
31.3%
patients with a post-treatment AHI < 5/hr is shown. For the
22.2% entire group and those with moderate and severe OSA, the
20%
OA was more effective in positional than in nonpositional
OSA. Note that the presence or absence of positional OSA was
most important in patients with a high pretreatment AHI (C).
0%
(A) Post-treatment AHI < 5 (B) AHI  10 to AHI <5 (C) AHI  20 to AHI <5
From Chung JW, Enciso R, Levendowski DJ, et al: Treatment
in total subjects outcomes of mandibular advancement devices in positional
and nonpositional OSA patients. Oral Surg Oral Med Oral Pathol
Positional OSA Non-positional OSA Oral Radiol Endod 2010;109:724731.

TABLE 202 expensive. OAs are now viewed by the U.S. Food and Drug
Attributes of an Ideal Oral Appliance Administration (FDA) as class 2 medical devices and, as
such, must adhere to more detailed standards with special
ATTRIBUTE COMMENT
controls.19 A short list of commonly used devices is pre-
Adjustable Allows for modification if dental work is sented in Table 203. A more extensive list is available in
needed. Reference 5. A list of FDA-approved devices can be found at
Titratable Ability to modify vertical opening or http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/
advancement of mandible. pmn.cfm
Full tooth Makes certain upper and lower teeth are
coverage fully engaged to prevent tooth Titration/Adjustment of OAs
movement.
After OAs are fabricated, they are usually adjusted by the
Posterior The upper and lower components dentist taking care of the patient for fit and comfort. Patients
support should have contact in the posterior
are then instructed to slowly increase mandibular protrusion
area for stabilization of TMJ.
until symptoms improve (cessation of snoring and improve-
Mandibular Allows free movement of mandible ment in sleep quality) or until either the maximum protru-
mobility during sleepbeneficial in patients sion is reached or further advances are not tolerated. In one
with bruxism. study, patients were studied during polysomnography (PSG)
Adequate lip Improves nasal breathing, prevents and a remotely controlled mandibular appliance was
seal drying of teeth. advanced until respiratory events were controlled or until
Adequate Prevents collapse of tongue into further advances were not tolerated.20 The results of the PSG
tongue space oropharyngeal airway. OA titration were highly predictive of the effectiveness of
TMJ = temporomandibular joint.
chronic OA treatment with a permanent device. In another
Adapted from Bailey DR, Hoekema A: Oral appliance therapy in sleep study, patients were allowed to adjust their devices at home.21
medicine. Sleep Med Clin 2010;5:9198. During a PSG if persistent events were noted, further adjust-
ment during the PSG was performed by protocol (increased
protrusion in 1-mm increments). Of the patients completing
come out during the night. However, the TSD (see Fig. 201) the protocol, 55% were successfully treated (AHI < 10/hr)
may be an affordable alternative for some patients. Purchase after home titration. A total of 64.9% of patients were suc-
of a TSD requires a prescription from a doctor or dentist cessfully treated overall. Thus, some patients will likely
(approximate price range is $125$180). need further adjustments either during or after a PSG
Some ideal attributes for an MRA are listed in Table 202. documenting the efficacy of OA treatment.
The ideal device has coverage of both arches and is adjustable
(protrusion can be changed). A recent study compared a
Adherence to OA Treatment
custom-made and thermoplastic OA for the treatment of
mild OSA. The custom-made device was more effective.18 Studies of adherence to OA treatment have almost always
However, custom-made devices are typically much more relied on patient report. There is a single report of the use
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354 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea

TABLE 203
Selected Oral Appliances
DEVICE TELEPHONE NUMBER WEBSITE
Tongue retaining device 800-828-7626
Tongue stabilizing device 800-854-7256 (United States) http://www.glidewelldental.com
Glidewell Dental is the authorized U.S. dealer.
TAP 866-AMI-SNOR http://www.TAPINTOSLEEP.COM
SUAD Herbst 888-447-6673
Klearway 800-828-7626 http://www.klearway.com
OASYS 888-866-2727 http://www.oasyssleep.com
FDA = U.S. Food and Drug Administration; OASYS = oral/nasal airway system; TAP = Thornton anterior positioner.
After Bailey DR, Hoekema A: Oral appliance therapy in sleep medicine. Sleep Med Clin 2010;5:9198.
See complete list on FDA website: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm

TABLE 204
Comparison of Oral Appliance and Continuous Positive Airway Pressure
TOTAL
NO. AHI ESS RX SUCCESS
CRITERION
AUTHOR N BASELINE CPAP MRA BASELINE CPAP MRA CPAP MRA (AHI#/hr)
Barnes, 104 21.3 12.8 4.8 4.7 14.0 10.1 10.2 4.7 9.2 3.8 9.2 3.7 Not stated 49% <10
200427
Clark, 23 33.9 14.3 11.2 3.9 19.9 12.8 52% 19% <10
199628
Engleman, 51 31 26 86 15 16 14 4 85 12 5 66% 47% <10
200229
Ferguson, 24 26.8 11.9 4.2 2.2 13.6 14.5 10.7 3.4 5.1 3.3 4.7 2.6 70% 55% <10 + SI
199725
Ferguson, 25 24.5 8.8 3.6 1.7 9.7 7.3 62% 48% <10 + SI
199626
Randerath, 20 17.5 7.7 3.2 2.9 13.8 11.1 100% 30% <10
200230
Tan, 24 22.2 9.6 31. 2.8 8.0 10.9 13.4 4.6 8.1 4.1 9.2 1 Not stated 67% <10
200231
AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure; ESS = Epworth Sleepiness Scale; MRA = mandibular repositioning appliance;
SI = symptoms improved.
From Ferguson KA, Cartwright R, Rogers R, et al: Oral appliances for snoring and obstructive sleep apnea: a review. Sleep 2006;29:244262.

of a temperature-sensitive embedded monitor to objectively
determine OA use.13 OA adherence rates tend to decrease
with the duration of use. One study reported 60% adherence
at 1 year and 48% at 2 years.22 Another study reported adher-
ence dropped from 82% to 62% over 4 years.23 The reasons
for discontinuing OA included side effects, complications,
and lack of efficacy. In a questionnaire study of OA patients
5 years after starting treatment, 64% of respondents were
using the OA. Of these, 93% were using the OA more than
4 nights/wk. Of those stopping OA treatment, the causes
were discomfort (44%), little or no effect (34%), and the
patient changing to CPAP treatment (23%).24 In two cross-
over studies of CPAP, adherence to OA was equal to or better
than to CPAP.25,26
Effectiveness Compared with Other Treatments
A number of studies have compared OSA and CPAP (Table
204).2531 They show that OAs are not as effective as CPAP
but are effective in a significant proportion of patients
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 Chapter 20
60
50
Apnea/hypopnea index
40
30
20
10
0 0
Pre-nCPAP
FIGURE 208 The AHI as determined by home monitoring before and after treatment with nasal continuous positive airway pressure (nCPAP;
left) and an anterior mandibular positioner (AMP; right). The AHI was significantly reduced (P < .05) by both devices, although the
posttreatment AHI was lower with nCPAP. From Ferguson KA, Ono T, Lowe AA, et al: A short-term controlled trial of an adjustable oral appliance
for the treatment of mild to moderate obstructive sleep apnoea. Thorax 1997;52:362368.
(1967%) (Fig. 208).1 In some studies listed in Table 204,
a significant proportion of patients preferred the OA to
CPAP. In some studies, improvement in daytime sleepiness
was similar with both OA and CPAP treatment even if the
AHI was higher with OA than with CPAP. In the study by
Barnes and colleagues27 using a cross-over design, 28% pre-
ferred CPAP, 41% preferred the OA, and 31% preferred
placebo (a tablet). In a study by Ferguson and associates,25
the compliance to an OA and CPAP were similar but patient
satisfaction was better with an OA.
OA Treatment Guidelines
The AASM practice parameters for the OA treatment of
patients with snoring and OSA2 are listed in Appendix 201.
The guidelines are summarized in Boxes 201 and 202. The
presence or absence of OSA must be determined before OA
treatment. It is important to determine whether OSA or
snoring is being treated. If OSA is present, the severity has
implications for treatment selection and the probability of
success with OA. The OA should be fitted by a qualified
dental professional. The treatment goals for snoring are to
reduce noise to an acceptable level. For OSA, treatment goals
are to reduce the AHI, improve oxygenation, and improve
sleep quality. OAs are indicated for primary snoring that
does not respond to simple measures such as weight loss,
lateral position, and treatment of nasal congestion. OAs are
also indicated for mild to moderate OSA. It is acknowledged
that CPAP may be more effective. CPAP rather than OA
should be the first treatment for severe OSA. If CPAP is not
accepted, upper airway surgery or an OA should be consid-
ered. Upper airway surgery may also supersede use of OA in
patients for whom surgery is predicted to be highly effective.
In patients with severe OSA who decline CPAP or surgery,
a trial of OA may be reasonable. Another indication for OA
would be patients who had failed surgery and do not want
CPAP or further surgery.
Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea 355
70
60
Apnea/hypopnea index
50
40
30
20
10
nCPAP Pre-AMP AMP
BOX 201
OA Treatment Guidelines
1. Initial diagnosis: Presence or absence of OSA must be
determined before OA treatment.
2. Appliance fitting: OA treatment should be managed by
dental practitioners with training in sleep medicine and
sleep-related breathing disorders.
3. Cephalometrics are not always needed, but if used,
qualified professionals should perform and evaluate.
4. Primary snoringGoal of OA is to reduce snoring to a
subjectively acceptable level.
5. OSAGoals of treatment are resolution of clinical signs
and symptoms of OSA, and normalization of the AHI and
arterial oxygen saturation.
6. OAs are indicated for treatment of primary snoring in
patients who do not respond to or are not appropriate
candidates for weight loss or sleep position change.
7. OA treatment is indicated for mild to moderate OSA
a. OA is not as efficacious as CPAP but is preferred by
some patients.
b. OA is indicated with CPAP failures.
c. OA treatment is indicated when there is failure of
weight loss or side sleep position treatments for
mild OSA.
8. OAs are not indicated for initial treatment of severe
OSA. Upper airway surgery may also supersede use of
OA in patients for whom surgery is predicted to be
highly effective.
AHI = apnea-hypopnea index; CPAP = continuous positive airway pressure;
OA = oral appliance; OSA = obstructive sleep apnea.
Adjustment of OA is usually preformed over days to
weeks with progressive protrusion until obvious apnea and
snoring have ceased or the limit of the device or patient
tolerance is reached. A study can then be performed to assess
efficacy. As noted in a later section, documentation of effi-
cacy with some type of sleep study is indicated for any level
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356 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
BOX 202
Follow-up after Oral Appliance Treatment
1. Follow-up sleep testing is not indicated after OA
treatment of primary snoring.
2. Follow-up sleep testing with the OA in place is
indicated after final adjustments of fit have been
performed.
All OSA severities.
PSG or attended type III cardiopulmonary test (PM)
(recent PM guidelines stated unattended portable
monitoring PM may be indicated for this purpose).
3. Follow-up visits with dental specialist until optimal fit
and efficacy are shown.
4. Follow-up dental visits every 6 months for first year, and
annually thereafter.
5. Regular visits with clinician supervising treatment of
OSA.
6. Repeat sleep study with OA in place if signs or
symptoms of OSA worsen or recur.
OA = oral appliance; OSA = obstructive sleep apnea; PM = portable
monitoring; PSG = polysomnography.
of OSA severity. For snoring alone, subjective improvement
may suffice.
Follow-up
The practice parameters do not mandate repeat sleep testing
for OA treatment of snoring. For all severities of OSA,
repeat sleep testing with the patient wearing the OA is indi-
cated to document effectiveness (see Box 202).2 The prac-
tice parameters state either PSG or an attended type 3
cardiopulmonary test is acceptable to assess the efficacy of
OA treatment. Recent clinical guidelines for portable moni-
toring (PM) also state that unattended PM may be indi-
cated to determine the adequacy of non-PAP treatment.32
In fact, either unattended cardiopulmonary monitoring or
attended PSG is usually used to determine the effectiveness
of OA treatment. Follow-up visits with the dentist who fab-
ricated the OA device are also indicated every 6 months,
then yearly. This is to ensure side effects are not significant
and the amount of protrusion is optimized. Follow-up with
the clinician directing sleep apnea treatment is also indicated
to be certain OSA symptoms are controlled and do not recur.
If symptoms return while the patient is using the OA,
repeat sleep testing with OA in place is indicated.
Centers for Medicaid and Medicare Services
Coverage of OA Treatment
The Centers for Medicaid and Medicare Services (CMS) has
recognized certain types of OAs as reasonable and necessary
for treatment of OSA. The criteria for reimbursement have
been published in the form of local carrier determinations
(LCDs) by Durable Medical Administrative Contractors
(DMACs). An excerpt from one LCD is listed in Appendix
BOX 203
Side Effects of Oral Appliance
1. Minor and temporary
a. Excessive salivation
b. Tooth pain
c. TMJ tenderness
d. Tongue pain (TSD/TRD)
2. Chronic and more severe
a. Tooth movement
b. TMJ dysfunction/pain
c. Gum disease
d. Dry mouth
TMJ = temporomandibular joint; TRD = tongue retaining device;
TSD = tongue stabilizing device.
202. Only custom-fabricated mandibular advancement OA
(E0486) devices are covered. Coverage requires a face-to-
face clinical evaluation prior to a Medicare-covered sleep
test. The patient must meet one of the following criteria: (1)
AHI 15/hr or respiratory disturbance index (RDI; events/
hr of monitoring time using a home sleep test) 15/hr or a
minimum of 30 events, (2) AHI (RDI) values 5 to 14 with
certain symptoms or disorders (see Appendix 202), AHI >
30 or RDI > 30 if the patient cannot tolerate a PAP device or
if the treating physician feels PAP treatment is contraindi-
cated. Note that testing for diagnosis cannot be performed
by the person or organization supplying the OA. The OA
device must be ordered by the treating physician following
review of the report of the sleep test. The device is provided
and billed for/by a licensed dentist (DDS or DMD). Custom-
fabricated devices that work by positioning of the tongue
(E1399) or a prefabricated OA (E0485) are not covered.
Side Effects and Complications
The available research suggests that side effects and compli-
cations (Box 203) may be grouped as follows: (1) minor and
temporary side effects and (2) moderate to severe and con-
tinuous side effects.
1. Minor and temporary side effects: These can occur at any
stage during treatment, are minor in severity, tend to
resolve in a short period of time, or are easily tolerated if
they do not resolve and they do not prevent regular use
of the appliance. Commonly reported minor and tempo-
rary side effects included TMJ pain, myofascial pain,
tooth pain, excessive salivation, TMJ sounds, dry mouth,
gum irritation, and morning-after occlusal changes. These
phenomena were observed in a wide range of frequencies
from 6% to 86% of patients.1 Patients undergoing TRD
and TSD treatments may report a sore tongue or difficulty
with the device slipping off during the night.
2. Moderate to severe and continuous side effects: These can
occur at any stage during treatment, are moderate to
severe in intensity, tend not to resolve over time, and may
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 Chapter 20
result in discontinuation of appliance use. More severe
and continuous side effects included TMJ pain, myofas-
cial pain, tongue pain (tongue devices only), gagging (soft
palate lifter mostly), tooth pain, gum pain, dry mouth,
and salivation.1 Occasionally, these phenomena prevent
continued use of the appliance. Several studies have found
long-term changes in dental occlusion but the results vary
between studies. The changes are relatively mild in most
patients. One study found occlusal changes after a mean
treatment duration of about 30 months.33 The anteropos-
terior position of the molars and the inclination of upper
and lower incisors changed with MRA treatment. No
skeletal changes in mandibular position were noted.
Combinations of OA with Other Treatments
Use of OSA in patients with persistent sleep apnea after
uvulopalatopharyngoplasty (UPPP) was reported by Millman
and coworkers34 in 18 patients. The post UPPP AHI was
37.2/hr and the arterial oxygen saturation (SaO2) nadir was
84%. With OA treatment, the AHI fell to 15.3/hr and the
SaO2 nadir was 87.9%. With the addition of a Herbst device,
10 of the patients had a fall in the AHI to less than 10/hr.
Effects of OA Treatment on Consequences of OSA
There have been few studies of the effects of OA treatment
of OSA on the cardiovascular consequences of OSA. Gotso-
poulos and colleagues35 found that OAs reduced blood pres-
sure in a randomized, controlled trial. Another study found
an improvement (normalization) of heart rate variability
after 3 months of OA treatment.36 More studies of the impact
of OAs are expected in the future.
SURGICAL TREATMENTS FOR OSA
Tracheostomy was the first treatment available for OSA.37
Since that time, a number of surgical options have become
available (Box 204).3841 These are more acceptable than
tracheostomy but none is more effective. Recently, a system-
atic review of surgical treatment options for treatment of
BOX 204
Surgical Options
BYPASSES ALL OBSTRUCTION
Tracheostomy
SELECTIVELY IMPROVES UPPER AIRWAY OBSTRUCTION
Nasal reconstruction
UPPP and LAUP
Genioglossus advancement
Hyoid advancement
MMA
Temperature-controlled RF tongue base reduction
LAUP = laser-assisted uvuloplasty; MMA = maxillomandibular
advancement; RF = radiofrequency; UPPP = uvulopalatopharyngoplasty.
Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea 357
OSA in adults and practice parameters have been published
by the AASM (Appendix 203).40,41
Evaluation for Possible Surgical Treatment
The typical evaluation of patients with snoring or OSA for
possible upper airway surgery includes fiberoptic examina-
tion of the nose, pharynx, and hypopharynx.42 Fiberoptic
pharyngoscopy while the patient performs a Mller maneu-
ver (inspiration with the nose occluded) is performed to help
identify the most prominent site of collapse (retropalatal or
retroglossal/hypopharyngeal area). A limitation of this tech-
nique, which is typically performed during wakefulness and
often in an upright posture, is that the results may not cor-
respond to what happens during supine sleep. Lateral cepha-
lometric radiographs are also standard and can help visualize
bony abnormalities and the posterior airspace. On cephalo-
metrics, OSA patients tend to have long soft palates, small
posterior air spaces (<10 mm behind the tongue), mandibu-
lar deficiency, and a long distance to the hyoid. The AASM
practice parameters for surgical treatment of OSA
mandate that all patients scheduled for surgery to correct
snoring or OSA should undergo PSG for diagnosis and to
assess severity.39,41
Indications for Surgical Treatment
The AASM practice parameters for surgical treatment of
OSA have recently been updated40,41 (see Appendix 203).
The practice parameters state that the presence and severity
of OSA must be determined before initiating surgical therapy.
The patient should be advised about the success of surgical
procedures and side effects as well as the success rate of
alternative treatments. The practice parameters state that
PAP should first be offered to patients with severe OSA and
either PAP or an OA for patients with moderate OSA.41 For
those requiring the stepped procedure approach, patients
should be informed that multiple surgical procedures may
be needed.39
Surgical Options
A number of surgical options are available (see Box 204).3848
Each is briefly discussed and then an overall approach is
presented.
Tracheostomy
This procedure bypasses all obstructions and is uniformly
effective at preventing upper airway obstruction.3741 Some
patients will still require supplemental oxygen, and some
patients with the obesity hypoventilation syndrome may con-
tinue to hypoventilate during sleep or require oxygen for
persistent nocturnal desaturation. The main use of tracheos-
tomy is for patients who have life-threatening OSA (often the
obesity hypoventilation syndrome with recurrent hypercap-
nic respiratory failure) and are poorly adherent to PAP treat-
ment. Another use is as a temporary measure while patients
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358 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
recover from other upper airway surgery. Tracheostomy is
cosmetically unacceptable to most patients. The indications
used in one large series included (1) disabling sleepiness with
severe consequences, (2) cardiac arrhythmias with sleep
apnea, (3) cor pulmonale, (4) AHI > 40/hr, (5) frequent
desaturations below 40%, and (6) no improvement after other
therapy.37 Recent AASM practice parameters state that tra-
cheostomy has been found to be an effective single interven-
tion.41 However, this operation should be considered only
when other options do not exist, have failed, are refused, or
when this operation is deemed necessary by clinical urgency.
Tracheostomy has significant complications in patients with
OSA.37,43 For example, anesthesia and intubation tend to be
more difficult in patients with large necks and narrow upper
airways. Postoperative complications include stoma infection/
granulation tissue, accidental decannulation, obstruction of
the tube when the head is turned or hyperextended, recurrent
purulent bronchitis, and psychosocial difficulties (depres-
sion).3739,43 Noncuffed, size 6 French tubes usually suffice. A
longer-than-usual tracheostomy tube may be needed for very
obese patients with thick necks. The end of the tracheostomy
tube typically is plugged during the day and, because of its
small size, air flows around it between the lungs and the
upper airway. If resistance to flow around the tube is a
problem, a fenestrated tube (hole at bend of the superior end
of the tube) may be used. During sleep, the tracheostomy
tube is unplugged to bypass the upper airway obstruction.
However, one must not forget that very obese patients can
still occlude the tracheostomy opening with triple chins.
Nasal Obstruction
Nasal obstruction can lead to mouth breathing during sleep.
This causes rotation of the mandible and retrodisplacement
of the tongue base back into the pharynx. The major areas
of focus include the nasal valve/alar cartilage area, septum,
and turbinates (mostly inferior turbinates). One study found
that radiofrequency ablation (RFA) of turbinate hypertrophy
can improve nasal CPAP adherence in selected patients.49
Long-term studies are needed to better define the indications
for this procedure. A randomized, controlled trial of nasal
surgery (vs. placebo surgery) found improvement in the
amount of nasal breathing during sleep (less mouth breath-
ing) but minimal effects on the AHI. The surgeries include
resection of the deviated nasal septum and submucous
FIGURE 209 Laser uvulopalatoplasty. A, Local anesthetic is
injected. B, The CO2 laser is used to excise vertical trenches of the
soft palate on either aspect of the uvula up to the muscular sling.
Thirty percent to 90% of the uvula is excised or vaporized. C, The
postoperative result necessitates 4 to 5 weeks for complete
healing and scarring to production traction forces to improve
airway patency. AC, From Li KK, Powell NB, Riley RW: Surgical
management of OSA. In Lee-Chiong TL, Sateia MJ, Carskadon
MA (eds): Sleep Medicine. Philadelphia: Hanley & Belfus, 2002,
p. 439, reproduced with permission.
A B
resection of the inferior turbinates.50 A review of the role of
the nose in the pathogenesis of OSA and snoring found no
published evidence to support the use of nasal surgery (cor-
rection of septal deviation or external valve collapse) as a
treatment of OSA.51 Thus, whereas nasal surgery can improve
the quality of life for some patients, it is considered as an
adjunctive rather than a primary treatment for OSA.
Palatal Implants
The Pillar procedure involves insertion of Teflon strips into
the palate and can be done in the office or outpatient surgery
center. The purpose of the strips is to stiffen the palate
(reduced snoring). The success is variable and sometimes
additional strip insertion is needed.40,5456 A randomized,
placebo-controlled study (sham implant procedure as
control) of palatal implants (PIs) in mild OSA found that the
AHI in both placebo and PI groups actually increased!53
Although the increase in the AHI was significantly less with
PI compared with control, this can hardly be seen as docu-
mentation of PI effectiveness. Snoring was slightly but sig-
nificantly improved more with PI than with control. Although
the evidence that palatal implant surgery is effective in
patients with OSA is very marginal, recent practice param-
eters stated Palatal implants may be effective in some
patients with mild OSA who cannot tolerate or are unwilling
to adhere to PAP therapy, or in whom oral appliances have
been considered and found ineffective or undesirable
(Option).41 Thus, PIs may be effective in some patients with
mild OSA but results are variable at best.
Laser-Assisted Uvuloplasty
Laser-assisted palatoplasty or uvuloplasty (LAP or LAUP)
was introduced recently as a treatment for snoring.46,5456 In
this procedure, only a small portion of the uvula/soft palate
is removed (Fig. 209). Usually two trenches on either side
of the uvula are cut. Some also remove the end of the uvula.
With time and scarring, the palate stiffens and elevates. This
procedure can be done on an outpatient basis using local
anesthesia. It is generally considered a treatment for snoring
but has been used for very mild sleep apnea when suitable
upper airway anatomy exists. The long-term efficacy of LAP
remains to be established. The standard of practice commit-
tee of the AASM was unable to recommend this procedure
for sleep apnea based on the current published evidence in
C
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 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea 359

2001.54 Recent practice parameters for surgical treatment of
OSA state LAUP is not routinely recommended as a treat-
ment for obstructive sleep apnea syndrome (Standard).41
Radiofrequency Ablation
Radiofrequency has been used in the upper airway with and
without temperature control of the probe tip. RFA has been
used for treatment of the soft palate, base of the tongue, and
treatment of multiple levels.40,46,47,56 Somnoplasty (a variant
of RFA) is a method of palatoplasty for treatment of snoring,
appears to be well tolerated (possibly less pain), but is no
more effective than traditional UPPP.40,56 It can be performed
as an outpatient procedure. Repeated treatments may be
needed. Several other procedures that utilize cautery or
injection of sclerotic agents to stiffen the palate have also
been used.46 The recent practice parameters for surgical
treatment of OSA state RFA can be considered as a treat-
ment in patients with mild to moderate OSA who cannot
tolerate or who are unwilling to adhere to PAP, or in whom
oral appliances have been considered and have been found
ineffective or undesirable (Option). RFA of the palate is not
more effective than traditional UPPP.
Uvulopalatopharyngoplasty
UPPP is an operation that removes residual tonsillar tissue,
the uvula, a portion of the soft palate, and redundant tissue
from the pharyngeal area (Fig. 2010).4648,57 Its disadvantages
include the need for general anesthesia and considerable
postoperative pain. The most frequent complication (Box
205) is velopharyngeal insufficiency, which is manifested as
some degree of nasal reflux when drinking fluids.5860 This
usually resolves within a month of surgery. Other potential
complications include voice change, postoperative bleeding,
nasopharyngeal stenosis (secondary to scarring), or a persis-
tent globus sensation. A few cases of severe postsurgical
bleeding or upper airway obstruction requiring reintubation
have been reported. It is prudent to admit patients to the
intensive care unit after surgery for close observation if sig-
nificant OSA is present. Significant apnea and desaturation
can occur during the recovery period in patients with
severe OSA. These problems often can be managed with
nasal CPAP.
However, the major problem with UPPP is less-than-
perfect efficacy as a treatment for OSA.40,41,61 UPPP does not
address airway narrowing behind the tongue or in the hypo-
pharynx; therefore, it is not universally effective in prevent-
ing sleep apnea. UPPP is generally reasonably effective in
decreasing the incidence or loudness of snoring (vibration
of the soft palate). In general, 40% to 50% of all patients
undergoing UPPP have about a 50% decrease in their AHI,
to less than 20/hr, or about a 30% chance of a postoperative
AHI dropping below 10/hr.38,40,60,61 The results will, of course,
depend on the presurgery AHI and the locations of upper
airway obstruction. Frequently, the number of apneas
decreases and the number of hypopneas increases after
UPPP. Of interest, one study of UPPP failures found the site
of upper airway obstruction to still occur at the retropalatal
area.62 Sasse and associates63 reported on a group of patients
in whom the AHI was actually higher after UPPP. Another
study reported that a significant number of initial responders
BOX 205
Complications from Uvulopalatopharyngoplasty
IMMEDIATE
Paincan be severe
Velopharyngeal incompetence (fluid out the nose during
swallowing)
Voice change
Globus sensationmucus in the back of the throat
Worsening of apnea in the postoperative period
DELAYED
Return of snoring
Worsening of OSA
Nasopharyngeal stenosis
Increased probability of mouth leak during CPAP treatment
CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea.

A B C
FIGURE 2010 Technique of uvulopalatopharyngoplasty. A, Redundant soft palate and tonsillar pillar mucosa
are outlined. B, Tonsils, tonsil pillar mucosa, and posterior soft palate are excised. The extent of the soft palate
excision is determined by placing traction on the uvula and noting the position of the mucosal crease. C, Mucosal
flaps of the lateral pharyngeal wall and nasal palatal muscle are advanced to the anterior pillar and/or mucosa of
the soft palate. The wound is closed with 3-0 polyglactin braided suture. AC, From Li KK, Powell NB, Riley RW:
Surgical management of OSA. In Lee-Chiong TL, Sateia MJ, Carskadon MA (eds): Sleep Medicine. Philadelphia: Hanley
& Belfus, 2002, p. 439, reproduced with permission.
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360 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
to UPPP may later relapse, especially if there is weight gain.64
Thus, patients treated with UPPP should be restudied if
symptoms or signs of sleep apnea return.
Recent practice parameters for surgical treatment of OSA
state UPPP as a sole procedure, with or without tonsillec-
tomy, does not reliably normalize the AHI when treating
moderate to severe OSA. Therefore, patients with severe
OSA should initially be offered positive airway pressure
therapy, while those with moderate OSA should initially be
offered either PAP therapy or oral appliances (Option).41
Several methods have been studied to determine whether
UPPP responders can be identified preoperatively. These
methods include cephalometric radiographs, computed axial
tomography, fluoroscopy, fiberoptic endoscopy of the upper
airway during Mller maneuvers (precipitating airway col-
lapse), and upper airway pressure monitoring during
sleep.42,62,64 In some of these methods, the patient is upright,
and in most, the patient is awake. Therefore, it is not surpris-
ing that predictions of what happens during sleep are less
than perfect. In general, patients with obstruction only in the
retropalatal area are the most likely to respond to UPPP.
However, no method can predict with certainty which
patients will benefit from this surgery. As previously noted,
a few studies have determined that the site of upper airway
obstruction in UPPP failures is the retropalatal area. Pre-
sumably, postsurgical changes secondary to either palatal
edema or scarring are to blame.62
UPPP is considered less effective than nasal CPAP because
it is less likely to eliminate apnea and normalize sleep.
However, when nasal CPAP is refused or not tolerated, UPPP
can be a treatment alternativeespecially in mild to moder-
ate apnea. With disease of this severity, there usually is a
reasonable chance of obtaining a postoperative AHI less than
15/hr. If UPPP fails, there is always the option of trying nasal
CPAP. However, one study suggested that when nasal CPAP
is used after UPPP, air leak via the mouth may be more
likely.65 Of interest, a retrospective study of a Veterans
Administration (VA) population found better survival in
patients after UPPP than treatment with CPAP.66 The study
was not adjusted for OSA severity or for the amount of CPAP
use. However, it does point out the need for prospective
FIGURE 2011 Technique of genioglossus ad-
vancement. A rectangular window of symphyseal
bone consisting of the geniotubercle is advanced
anteriorly, rotated to allow body overlap, and im-
mobilized with a titanium screw. Left, Anterior
view. Right, Lateral view. From Li KK: Hypoglossal
airway surgery. Otolaryngol Clin North Am 2007;
40:845853.
long-term evaluation of relative UPPP efficacy compared
with CPAP.
Uvulopalatal Flap
This surgery is a modification of the UPPP and, instead of
removing the uvula and soft palate, the uvula is retracted and
tucked superiorly under the soft palate. The pharyngeal
pillars are sutured back and tonsils are removed in this pro-
cedure as well. The advantages are less postoperative pain
and perhaps less nasopharyngeal reflux. The results are
similar to UPPP. The procedure cannot be done if the palate
is very long or bulky.45,47
Genioglossus Advancement/Hyoid Advancement
In the genioglossus advancement (GA) (Fig. 2011), the
attachment of the genioglossus at the genoid tubercle of the
mandible is advanced by making a limited rectangular man-
dibular osteotomy to include the genial tubercle (site of
attachment of genioglossus and geniohyoid on the mandi-
ble).38,40,44,45,48 The rectangular piece of bone with muscular
attachments is advanced and rotated to prevent retraction of
the piece of bone back into the mandible. A screw is then
placed for stabilization.
When initially introduced, the second component of the
surgery, hyoid advancement (HA) (Fig. 2012) was called
hyoid myotomy with suspension. The original surgery con-
sisted of release of the hyoid from its inferior muscular
attachments and suspension from the anterior mandible
with suture or ligament. Today, the hyoid is often attached
to the superior border of the thyroid cartilage. This modifica-
tion has increased the response rate to approximately 80%.
Some surgeons perform only the GA at the first surgery with
the HA performed only if needed at a subsequent operation.
The GAHA does not require any change in dental occlusion.
Complications of GAHA include transient anesthesia of
the lower anterior teeth (all) and, rarely, tooth injury. Indica-
tions for GAHA include a small posterior airspace by
lateral cephalometrics (<10 mm), an increased mandible-to-
thyroid distance (>20 mm) by cephalometrics, mandibular
deficiency, tongue base prominence on nasopharyngoscopy,
or macroglossia.44
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 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
The recent AASM practice parameters for surgical treat-
ment of OSA did not provide a specific statement about the
GA or HA procedures. The practice parameters state mul-
tilevel or stepwise surgery (MLS), as a combined procedure
or stepwise operations, is acceptable in patients with narrow-
ing of multiple sites in the upper airway, particularly if they
have failed UPPP as a sole treatment (Option).41
Maxillomandibular Advancement
Maxillomandibular advancement (MMA) is a complex
upper airway surgery, but excluding tracheostomy, this pro-
cedure has the best record of success as a treatment for OSA
(Fig. 2013). The maxilla and mandible are advanced
together and both upper and lower teeth are moved to main-
tain adequate occlusion.44,45,48,67 The procedure increases the
retrolingual and, to a small extent, the retropalatal segments
of the upper airway. The maxilla is moved by a Le Fort I
osteotomy and the mandible by a sagittal split osteotomy.
Numbness of the chin and cheek areas is an expected com-
plication that resolves in 6 to 12 months in most patients.
The indications for MMA are listed in Box 206. In some
361
FIGURE 2012 Technique of hyoid advancement
(HA). The hyoid bone is isolated, the inferior body is
dissected clean, and the majority of the suprahyoid
musculature remains intact. The hyoid is advanced
over the thyroid lamina and immobilized with
sutures placed through the superior aspect of the
thyroid cartilage. Left, Anterior view. Right, Lateral
view. From Li KK: Hypoglossal airway surgery.
Otolaryngol Clin North Am 2007;40:845853.
FIGURE 2013 Technique of maxillomandibular advance-
ment osteotomy procedure (lateral view). Le Fort I maxillary
osteotomy with rigid plate fixation and a bilateral sagittal
split mandibular osteotomy with bicortical screw fixation. The
advancement is at least 10 mm. From Li KK: Hypoglossal
airway surgery. Otolaryngol Clin North Am 2007;40:845853.
BOX 206
Indications for Maxillomandibular Advancement
FIRST SURGICAL OPTION
Severe OSA (especially with minimally redundant palate)
Retrognathia or facial skeletal deficiency
Morbid obesity
Adequate health to undergo surgery
SECOND SURGERY
Failed previous surgical procedures
OSA = obstructive sleep apnea.
institutions, MMA is performed only after UPPP and GAHA.
For patients with severe OSA and/or mandibular deficiency,
MMA can also be offered as the initial surgery. If the palate
is long, doing a UPPP at the same time as the MMA is also
an option.
The MMA enlarges the pharyngeal and hypopharyngeal
areas by moving the skeletal framework and tensions the
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362 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
suprahyoid and velopharyngeal musculature. Whereas
patients with retrognathia may be especially good candi-
dates, this procedure does not require that patients have this
problem.
MMA Procedure The maxillary procedure is a Le Fort I oste-
otomy above the apices of the upper teeth. The maxilla is
advanced 10 to 12 mm and stabilized with plates. The man-
dibular procedure involves a sagittal split osteotomy. The
medial and lateral cortex of the mandible is separated at the
ramus region with care to preserve the inferior alveolar
nerve. The dentated mandibular segment is then advanced
to align with the maxilla and rigid fixation is performed with
screws or plates.
Outcomes of MMA Response rates up to 90% have been
publisheddepending on the definition of surgical success.
Li and coworkers67 reported 95% cure rate defined as an
AHI < 20/hr and at least a 50% reduction. In a group of
patients who responded to MMA (36 of 40 studied), the AHI
dropped from 69.6/hr preoperatively to 7.7/hr postopera-
tively. A recent meta-analysis found MMA to reduce the AHI
to less than 20/hr in 80% to 90%.61 This procedure is usually
offered only at large tertiary hospitals by experienced maxil-
lofacial surgeons. The recent AASM practice parameters for
surgical treatment of OSA state MMA is indicated for surgi-
cal treatment of severe OSA in patients who cannot tolerate
or are unwilling to adhere to positive airway pressure therapy,
or in whom oral appliances, which are often more appropri-
ate in mild and moderate OSA patients, have been consid-
ered and found ineffective or undesirable (Option).41 The
reason for the grade of Option rather than a higher grade of
Guideline is that the published studies were considered low
quality of evidence because they were small and not con-
trolled. Other than tracheostomy, the procedure is most
likely to significantly improve the AHI in patients with
severe OSA, although the AHI is often not normalized. Of
note, there are individual patients with severe OSA in whom
OA treatment may be equally effective.
Tongue Procedures
In an attempt to avoid surgery involving the mandible or
maxilla, procedures directed at the tongue have also been
developed.45,46,68 Laser midline glossectomy (LMG) and lin-
gualplasty (LP) increase the retroglossal airway by removing
tongue tissue. When combined with UPPP, the procedures
are known collectively as UPPGP or UPPLP. Due to a number
of side effects including postoperative bleeding, odynopha-
gia, and alterations in speech, these are rarely performed
today. Temperature-controlled radiofrequency tongue base
reduction has also been used to reduce the retroglossal
obstruction. Serial treatments are usually required. Side
effects have included a single report of a tongue abscess and
temporary pain on swallowing or local ulceration. An initial
study showed the AHI improved from 39.6/hr to 17.9/hr.68
However, long-term follow-up showed relapse (AHI =
28.7/hr) without major weight gain. This procedure is usually
used as an adjunctive measure with other procedures. After
the first procedure, subsequent procedures are often done in
an outpatient surgery center.
Tongue Base Suspension Suture A suspension suture is looped
from an anchor screw on the inner surface of the mandible
to the base of the tongue. The suture is tensioned, bringing
the tongue forward. The procedure can be performed in less
than 1 2 hour and has few side effects (infection, injury to
tooth roots, and detachment of screw). The success rates are
variable.69 The procedure is often performed with a UPPP or
another procedure.
Overall Surgical Approach
The overall surgical approach depends on OSA severity,
upper airway anatomy, prior treatment failures, and patient
preference. Box 207 presents a summary of recommenda-
tions from recent surgical practice parameters. One approach
to treatment is to classify patients as type 1 to 3. Obstruction
can be classified as type 1 to 3 based on the predominant
level of upper airway obstruction.44,46 A type 1 obstruction is
at the retropalatal area. Type 3 obstruction is at the hypo-
pharyngeal area (behind the tongue or lower), and type 2 is
a combined obstruction (palate + hypopharynx). Type 1
patients are considered favorable candidates for palatal
BOX 207
Surgical Practice Parameter Recommendations
PROCEDURE INDICATIONS/CONDITIONS
Tracheostomy Other options do not exist or have failed.
Clinical urgency (e.g., repeated bouts of
hypercapnic respiratory failure).
MMA Severe OSA.
Unwilling or unable to tolerate PAP.
OA considered and undesirable or
ineffective.
UPPP Snoring, mild OSA.
Moderate OSAonly after offering PAP
treatment and OAs.
Palatal May be effective in some patients with
implants mild OSA.
Indicated for OSA treatment IF patients
cannot tolerate/adhere to PAP therapy
and OA treatment is considered and
found ineffective and undesirable.
Multilevel or Upper airway narrowing at multiple
stepwise sites.
surgery Have failed UPPP as sole treatment.
MMA = maxillomandibular advancement; OA = oral appliance;
OSA = obstructive sleep apnea; PAP = positive airway pressure;
UPPP = uvulopalatopharyngoplasty.
From Caples SM, Rowley JA, Prinsell JR, et al: Surgical modifications of the
upper airway for obstructive sleep apnea in adults: a systematic review
and meta-analysis. Sleep 2010;33:13961407.
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 Chapter 20
Presurgical evaluation
(Physical examination,
cephalometric analysis,
fiberoptic pharyngoscopy)
Phase I (site of obstruction)
UPPP UPPP  GAHA
(Type 1 - retropalatal) (Type 2 - retropalatal-hypopharynx)
Post-operative PSG (6 mo)
(Failure)
Phase II
MMA
procedures (UPPP). Type 3 are candidates for procedures
addressing the retroglossal space (GA, with or without HA
[also called hypoid myotomy], or MMA). Type 2 patients are
candidates for combined UPPP and GAHA or MMA. A
systematic stepped surgical approach has been advocated
such as the one used at Stanford (Fig. 2014).44,46 A postop-
erative PSG is performed in 6 months and treatment failures
can then be offered MMA. Because an occasional patient
with type 2 obstruction will improve with UPPP, in some
centers, a retrolingual procedure is added only after UPPP
fails. In some other centers, patients with severe OSA, severe
mandibular deficiency, or very small posterior air spaces are
offered MMA with or without UPPP as the first procedure.
Some patients also want to avoid multiple procedures and
this more aggressive approach may be more acceptable
to them.
Success Rates of Upper Airway Surgery
A recent meta-analysis and synthesis of evidence for success
in upper airway surgery was reported by Elshaug and col-
leagues61 (Table 205). A traditional metric of success has
been a 50% reduction in the AHI and/or 20/hr or less. These
authors suggested a more rigorous approach with reduction
less than 10 or 5/hr being the goal of success. Phase I surgery
included palatal surgery with or without other procedures
such as GA or GAHA. Phase II surgery was the MMA with
or without additional procedures. Of course, the percentage
termed successful will depend on the initial severity.
SURGERY FOR PEDIATRIC OSA
Tonsillectomy and Adenoidectomy
Tonsillectomy and adenoidectomy (TNA) has been the stan-
dard treatment for OSA in pediatric patients for many years
Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea 363
FIGURE 2014 Stepped surgical approach to
treatment of obstructive sleep apnea (OSA) based
on the site of upper airway obstruction. GAHA =
genioglossal advancement/hyoid advancement;
MMA = maxillomandibular advancement; PSG =
polysomnography; UPPP = uvulopalatopharyngo-
plasty. Adapted from Li KK, Powell NB, Riley RW:
Surgical management of obstructive sleep apnea. In
GAHA Lee-Chiong TL, Sateia MJ, Caraskadon MA (eds):
(Type 3-hypopharynx) Severe OSA Sleep Medicine. Philadelphia: Hanley & Belfus,
2002, pp. 435446.
Retrognathia
Patient wants only
one procedure
TABLE 205
Meta-analysis Results for Upper Airway Surgery
(% Success Rates)
50% REDUCTION
IN AHI AND/OR AHI AHI
CRITERIA TO 20/HR < 10/HR < 5/HR
Phase I* 55% 31.5% 13%
Phase II 86% 45% 43%
*Phase I (UPPP, GA, HA, or combination).
Phase II (MMA).
GA = genioglossus advancement; HA = hyoid advancement; MMA =
maxillomandibular advancement; UPPP = uvulopalatopharyngoplasty.
From Elshaug AG, Moss JR, Southcott A, et al: Redefining success in airway
surgery for obstructive sleep apnea: a meta-analysis and synthesis of the
evidence. Sleep 2007;30:461467.
(Fig. 2015). There are over 400,000 surgeries per year. It is
estimated that PSG is performed in only about 10% of
patients undergoing TNA.70 Studies have shown that history
and physical examination are not accurate in predicting the
presence or absence of OSA. The size of tonsils is not predic-
tive of OSA. However, the need for routine PSG before
TNA for childhood sleep apnea is still debated.70,71 Both the
American Academy of Pediatrics72 and the American Tho-
racic Society73 recommend preoperative PSG.
Earlier studies found that TNA successfully eliminated
OSA in 75% to 100% of patients. Recent prospective studies
using postoperative PSG have found lower cure rates
(depending on the definition of success).7477 A prospective
study of 199 children with OSA found 46% continued to
have elevated AHI (AHI > 1/hr) on follow-up PSG per-
formed 3 to 5 months later.74 A high Mallampati score (3 or
4), turbinate hypertrophy, retroposition of the mandible, and
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364 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
FIGURE 2015 Tonsillectomy and adenoi-
dectomy. The adenoid and tonsillar tissues are
removed and the lateral pharyngeal walls are
sutured to prevent collapse. From Won CHJ, Li
KK, Guilleminault C: Surgical treatment of
obstructive sleep apnea. Proc Am Thorac Soc
2008;5:193199.
a deviated septum were predictive of an elevated postopera-
tive AHI.74 Another study of a cohort of 110 children found
complete normalization of AHI was present in only 25% of
patients.75 A meta-analysis by Brietzke and Gallagher76 found
82% of patients to be successfully treated for OSA. In the
studies analyzed, treatment success varied between studies
(AHI < 15/hr). Another meta-analysis of the efficacy of
TNA by Friedman and associates77 found cure, defined as
an AHI < 1/hr, to occur in about 60% of patients. Most
patients undergoing TNA do improve symptomatically, but
frequently significant residual OSA is still present. TNA is
still considered the initial treatment of choice in pediatric
patients with OSA. A postsurgery PSG is recommended and
other treatments (including weight reduction or CPAP) may
be needed. Complications from the TNA include bleeding,
pain, infection, and weight loss.72,73,78
Performing a PSG before TNA has a number of advan-
tages: (1) accurate diagnosis and avoiding unnecessary
surgery, (2) PSG results provide parents with an estimate
of chance of success; patients with an elevated AHI may
require additional treatment beyond TNA, and (3) the
PSG and clinical evaluation may reveal factors indicating
increased risk for postoperative complications. These
patients require overnight or at least extended monitoring
of the SaO2. Proposed risk factors for TNA requiring over-
night hospitalization or more long-term recovery room
monitoring are listed in Box 208.72,78 Nasal CPAP can be
used to manage postoperative complications in very severely
affected individuals. The need for routine postoperative
PSG in patients who have undergone TNA (after surgical
healing) is also a subject of controversy.70,71 A PSG is defi-
nitely indicated if signs or symptoms of OSA continue or
return after a period of improvement. One can also make a
case for a postoperative PSG in patients with moderate or
severe OSA (AHI of 510 or > 10/hr, respectively) or sig-
nificant obesity.
Rapid Maxillary Expansion
Rapid maxillary expansion (RME) in conjunction with
TNA has been shown to be successful in treating children
with OSA and maxillary contraction (high arched palate
BOX 208
Criteria for Increased Risk of Tonsillectomy and
Adenoidectomy
CLINICAL CRITERIA
Age < 2 yr
Craniofacial abnormalities affecting the pharyngeal airway
(especially midface hypoplasia or micro-/retrognathia)
Failure to thrive
Hypotonia
Cor pulmonale
Morbid obesity or daytime hypercapnia
Previous upper airway trauma
Undergoing a UPPP in addition to TNA
PSG CRITERIA
AHI > 40/hr
SaO2 nadir < 70%
SaO2 = arterial oxygen saturation; TNA = tonsillectomy and
adenoidectomy; UPPP = uvulopalatopharyngoplasty.
From Rosen GM, Muckle RP, Mahowald MW, et al: Postoperative respiratory
compromise in children with obstructive sleep apnea syndrome: can it be
anticipated? Pediatrics 1994;93:784788.
and unilateral or bilateral cross-bite).7981 RME requires an
orthodontic device (Fig. 2016) anchored to two upper
molars on each side of the jaw that applies daily pressure
causing each half of the maxilla to grow apart. This technique
aims to expand the hard palate laterally, raise the soft palate,
and widen the nasal passages. RME needs to occur before
cartilage becomes bone (516 yr of age). Distraction osteo-
genesis is defined as the mechanical induction of new bone
between two bony surfaces that are gradually distracted
(separated). If RMD is not successful or deemed insufficient,
mandibular distraction osteogenesis is performed surgically.
A surgeon uses a saw to create osteotomies in the mandible
and then either an internal or an external device is used to
expand the bones. Mandibular distraction osteogenesis is
often used to treat sleep apnea in patients with severe
congenital abnormalities of the mandible (micrognathia)
as in the Treacher Collins syndrome or Pierre Robin
syndrome.82
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 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea 365

FIGURE 2016 Occlusal sequence of treatment with rapid maxillary expansion from crowding in the upper central incisors (top)
to a wide space (bottom). Note how the palatal vault has changed. From Pirelli P, Saponara M, Guilleminault C: Rapid maxillary
expansion in children with obstructive sleep apnea syndrome. Sleep 2004;27:764.

CLINICAL REVIEW QUESTIONS C. Palatal surgery, PSG only if symptoms appear.

1. A 53-year-old man was diagnosed with moderate OSA D. OA rather than PI treatment, PSG if symptoms appear.
with an AHI of 20/hr about 4 years ago. He underwent a
4. A 35-year-old man has moderate OSA with an AHI of 20/
UPPP and a postoperative PSG showed an AHI of 8/hr.
hr. Fiberoptic examination of the upper airway with the
He noted resolution of snoring and daytime sleepiness.
Mller maneuver demonstrates obstruction at both the
Recently, he began to have return of his daytime sleepi-
retropalatal and the retroglossal areas. What surgery do
ness, although minimal snoring is present. No weight
your recommend?
gain has been noted. What do you recommend?
A. UPPP + GAHA.
A. An OA.
B. UPPP.
B. PSG.
C. GAHA.
C. Modafinil.
D. MMA.
D. Weight loss.

2. An 11-year-old male has a history of snoring and daytime 5. Of the following factors, which is predictive of a good
sleepiness. On physical examination, he is obese (BMI = response to an OA?
30) and has 4+ enlarged tonsils. A sleep study shows an A. Higher BMI.
AHI of 20/hr with all events being obstructive apneas or B. Mild retrognathia.
hypopneas. What treatment do you recommend? C. Presence of postural OSA.
A. TNA. D. Rapid eye movementrelated OSA.
B. CPAP.
C. Weight loss. 6. A 40-year-old woman has loud snoring and mild OSA
(AHI 10/hr). She also has nasal congestion with septal
D. UPPP.
deviation and hypertrophy of the inferior turbinates. She
3. A 40-year-old man with loud snoring but no witnessed has good dentition and no TMJ problems. Her orophar-
apnea or daytime sleepiness is considering the palatal ynx is a Mallampati 2, and she has a long uvula. Which
implant surgery for snoring. He is seeking a second of the following treatment options do you recommend?
opinion. What do you recommend? A. LAUP.
A. PSG; if OSA is present, PI surgery not indicated. B. Nasal surgery.
B. Proceed with palatal surgery but obtain postproce- C. OA.
dure PSG. D. OA or UPPP
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366 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea
7. A 40-year-old man has severe daytime sleepiness and an
AHI of 40/hr with moderate arterial oxygen desaturation.
The patients only medical problems are obesity and
hypertension. Multiple attempts at PAP treatment have
been unsuccessful. Which treatment alternatives do you
recommend?
A. UPPP.
B. UPPP + GAHA.
C. MMA.
D. OA.
Answers
1. B. Recurrence of OSA following initial success after
UPPP has been reported even without weight gain. In
this patient, a PSG is indicated to determine whether
OSA has returned and, if so, the severity. The cause of
the daytime sleepiness should be determined before
treatment.
2. A. Although this patient is at risk of having considerable
postoperative OSA, a TNA is still the first-line treatment
in pediatric patients unless minimal tonsillar tissue is
present. A postoperative PSG is essential to rule out sig-
nificant residual OSA (even if symptoms improve).
3. A. A PSG is indicated to determine whether primary
snoring or OSA is present. This is true whether the patient
undergoes upper airway surgery or treatment with an
OA. If moderate OSA is present, PI surgery is not indi-
cated. If mild OSA is present, PI is indicated with reserva-
tions. The surgical practice parameters state palatal
implants may be effective in some patients with mild OSA
who cannot tolerate or are unwilling to adhere to PAP
therapy, or in whom oral appliances have been considered
and found ineffective or undesirable. If mild OSA is
present, an OA will likely be more effective for both
snoring and OSA. If PI or OA treatment is used to treat
OSA, a post-treatment PSG (after surgical healing or with
the OA in place after adjustment) is indicated. The type
of treatment that is indicated will depend on the severity
of OSA and the patients preference.
4. A. The combined surgery is indicated in patients with
obstruction in both retropalatal and retroglossal areas.
The MMA might be effective but, because the patient is
not severe, this would not usually be the first surgical
option. In the step approach, this would be considered
only if phase I surgery was not successful.
5. C. Patients with postural OSA usually have a better
response to OA therapy.
6. E. An LAUP is not indicated for OSA. Nasal surgery
would be considered adjunctive. Either an OA or a UPPP
would be a reasonable treatment alternative.
7. C. In patients with severe OSA in whom PAP treatment
has failed (or not tolerated), the treatment options include
OA and MMA. Given the severity of symptoms and
desaturation, MMA is indicated. OA can be effective in
some patients with severe OSA. If the patient declines
surgery or is not a good surgical candidate, then OA treat-
ment may be the best option.
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palatopharyngoplasty. Otolaryngol Head Neck Surg 1981;
89:923934.
58. Larsson LH, Carlsson-Norlander B, Svanborg E: Four year
follow-up after uvulopalatopharyngoplasty in 50 unselected
patients with obstructive sleep apnea syndrome. Laryngoscope
1994;104:13621368.
59. Fairbanks DNF: Uvulopalatopharyngoplasty complications
and avoidance strategies. Otolaryngol Head Neck Surg 1990;
102:239245.
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60. Franklin KA, Anttla H, Axelsson S, et al: Effects and side-effects
of surgery for snoring and OSA: a systematic review. Sleep
2009;32:2736.
61. Elshaug AG, Moss JR, Southcott A, et al: Redefining success in
airway surgery for obstructive sleep apnea: a meta-analysis and
synthesis of the evidence. Sleep 2007;30:461467.
62. Hudgel DW, Harasick T, Katz RL, et al: Uvulopalatopharyngo-
plasty in obstructive apnea: value of preoperative localization
of site of upper airway narrowing during sleep. Am Rev Respir
Dis 1991;143:942946.
63. Sasse SA, Mahutte CK, Dickel M, Berry RB: The characteristics
of five patients with obstructive sleep apnea whose apnea-
hypopnea index deteriorated after uvulopalatopharygoplasty.
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64. Launois SH, Feroah TR, Campbell WN, et al: Site of pharyngeal
narrowing predicts outcome of surgery for obstructive sleep
apnea. Am Rev Respir Dis 1993;147:182189.
65. Mortimore IL, Bradley PA, Murray JAM, Douglas NJ: Uvulo-
palatoplasty may compromise nasal CPAP therapy in sleep
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66. Weaver EM, Maynard C, Yueth B: Survival of veterans with
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68. Li K, Powell NB, Riley RW, Guilleminault C: Temperature con-
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dered breathing: long term outcomes. Otolaryngol Head Neck
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69. Miller FR, Watson D, Malis D: Role of tongue base suspension
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Head Neck Surg 2002;126:392398.
70. Hoban TF: Polysomnography should be required both before
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71. Friedman N: Polysomnography should not be required before
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74. Guilleminault C, Huang YS, Glamann C, Chan A: Adenotonsil-
lectomy and obstructive sleep apnea in children: a prospective
survey. Otolaryngol Head Neck Surg 2007;136:169175.
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tive sleep apnea syndrome in children after adenotonsillec-
tomy. J Pediatr 2006;121:803808.
76. Brietzke SE, Gallagher D: The effectiveness of tonsillectomy
and adenoidectomy in the treatment of pediatric obstructive
sleep apnea/hypopnea syndrome: a meta-analysis. Otolaryngol
Head Neck Surg 2006;134:979984.
77. Friedman M, Wilson M, Chang HW: Updated systematic
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pediatric obstructive sleep apnea/hypopnea syndrome. Otolar-
yngol Head Neck Surg 2009;140:800808.
78. Rosen GM, Muckle RP, Mahowald MW, et al: Postoperative
respiratory compromise in children with obstructive sleep
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784788.
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sion in children with obstructive sleep apnea syndrome. Sleep
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80. Cistulli PA, Palmisano RG, Poole MD: Treatment of obstructive
sleep apnea syndrome by rapid maxillary expansion. Sleep
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in children with obstructive sleep apnea syndrome: 12-month
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dren with craniofacial deformities. Plast Reconstr Surg 1998;
101:312318.
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Summary of AASM Practice Parameters for the
Use of Oral Appliances for Treatment of Snoring
and Obstructive Sleep Apnea
3.1 Diagnosis
3.1.1 The presence or absence of OSA must be determined
before initiating treatment with OAs to identify those
patients at risk due to complications of sleep apnea and to
provide a baseline to establish the effectiveness of subsequent
treatment. Detailed diagnostic criteria for OSA are available
and include clinical signs, symptoms, and the findings iden-
tified by polysomnography. The severity of sleep-related
respiratory problems must be established in order to make
an appropriate treatment decision. (Standard)
3.2 Appliance Fitting
3.2.1 OAs should be fitted by qualified dental personnel
who are trained and experienced in the overall care of oral
health, the temporomandibular joint, dental occlusion, and
associated oral structures. Dental management of patients
with OAs should be overseen by practitioners who have
undertaken serious training in sleep medicine and/or sleep-
related breathing disorders with focused emphasis on the
proper protocol for diagnosis, treatment, and follow-up.
(Option)
3.2.2 Although cephalometric evaluation is not always
required for patients who will use an OA, appropriately
trained professionals should perform these examinations
when they are deemed necessary. (Option)
3.3.1 Treatment Objectives
3.3.1.1 For patients with primary snoring without features of
OSA or upper airway resistance syndrome, the treatment
objective is to reduce the snoring to a subjectively acceptable
level. (Standard)
3.3.1.2 For patients with OSA, the desired outcome of
treatment includes the resolution of the clinical signs and
symptoms of OSA and the normalization of the apnea-
hypopnea index and oxyhemoglobin saturation. (Standard)
3.3.2 OAs are appropriate for use in patients with primary
snoring who do not respond to or are not appropriate can-
didates for treatment with behavioral measures such as
weight loss or sleep position change. (Guideline)
Appendix 20-1
3.3.3 Although not as efficacious as CPAP, OAs are indi-
cated for use in patients with mild to moderate OSA who
prefer OAs to CPAP, or who do not respond to CPAP, are not
appropriate candidates for CPAP, or who fail treatment
attempts with CPAP or treatment with behavioral measures
such as weight loss or sleep position change. (Guideline)
3.3.4 Patients with severe OSA should have an initial trial
of nasal CPAP because greater effectiveness has been shown
with this intervention than with the use of OAs. Upper
airway surgery (including tonsillectomy and adenoidectomy,
craniofacial operations, and tracheostomy) may also super-
sede use of OAs in patients for whom these operations are
predicted to be highly effective in treating sleep apnea.
(Guideline)
3.4 Follow-up
3.4.1 Follow-up sleep testing is not indicated for patients
with primary snoring. (Guideline)
3.4.2 To ensure satisfactory therapeutic benefit from OAs,
patients with OSA should undergo polysomnography or an
attended cardiorespiratory (type 3) sleep study with the OA
in place after final adjustments of fit have been performed.
(Guideline)
3.4.3 Patients with OSA who are treated with OAs should
return for follow-up office visits with the dental specialist.
Once optimal fit is obtained and efficacy shown, dental spe-
cialist follow-up at every 6 months is recommended for the
first year, and at least annually thereafter. The purpose of
follow-up is to monitor patient adherence, evaluate device
deterioration or maladjustment, evaluate the health of the
oral structures and integrity of the occlusion, and assess the
patient for signs and symptoms of worsening OSA. Intoler-
ance and improper use of the device are potential problems
for patients using OAs, which require patient effort to use
properly. OAs may aggravate temporomandibular joint
disease and may cause dental misalignment and discomfort
that are unique to each device. In addition, OAs can be ren-
dered ineffective by patient alteration of the device. (Option)
3.4.4 Patients with OSA who are treated with OAs should
return for periodic follow-up office visits with the referring
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370 Chapter 20 Oral Appliance and Surgical Treatment for Obstructive Sleep Apnea

clinician. The purpose of follow-up is to assess the patient patient care. An objective re-evaluation of respiration during
for signs and symptoms of worsening OSA. Close commu- sleep is indicated if signs or symptoms of OSA worsen or
nication with the dental specialist is most conducive to good recur. (Option)

CPAP = continuous positive airway pressure; OA = oral appliance; OSA = obstructive sleep apnea.
From Kushida CA, Morgenthaler TI, Littner MR, et al: American Academy of Sleep Medicine. Practice parameters for the treatment of snoring and
obstructive sleep apnea with oral appliances: an update for 2005. Sleep 2006;29:240243.
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Excerpts from Local Coverage Determination
for Oral Appliances for Obstructive
Sleep Apnea (L28606)
A custom-fabricated mandibular advancement oral appli-
ance (E0486) used to treat obstructive sleep apnea (OSA) is
covered if criteria AD are met.
A. The patient has a face-to-face clinical evaluation by the
treating physician prior to the sleep test to assess the
patient for OSA testing.
B. The patient has a Medicare-covered sleep test that meets
one of the following criteria (13):
1. The apnea-hypopnea index (AHI) or respiratory dis-
turbance index (RDI) 15 events/hr with a minimum
of 30 events; or
2. The AHI or RDI 5 and 14 events/hr with a
minimum of 10 events and documentation of
a. Excessive daytime sleepiness, impaired cognition,
mood disorders, or insomnia; or
b. Hypertension, ischemic heart disease, or history of
stroke, or
3. If the AHI > 30 or the RDI > 30 and meets either of
the following (a or b):
a. The patient is not able to tolerate a positive airway
pressure (PAP) device, or
b. The treating physician determines that the use of a
PAP device is contraindicated.
Note: Here AHI = apnea + hypopnea index (hypopnea = 30% drop in flow + 4% desaturation).
RDI is determined by a type 3 or type 4 home sleep test (RDI = apneas + hypopneas/hour of monitoring time).
Available at Noridian https://www.noridianmedicare.com/dme/coverage/docs/lcds/current_lcds/oral_appliances.htm%3f
Appendix 20-2
C. The device is ordered by the treating physician following
review of the report of the sleep test. (The physician who
provides the order for the oral appliance could be differ-
ent from the one who performed the clinical evaluation
in criterion A.)
D. The device is provided and billed for by a licensed dentist
(DDS or DMD).
If all of these criteria (AD) are not met, the custom-
fabricated oral appliance (E0486) will be denied as not rea-
sonable and necessary.
Custom-fabricated appliances that achieve their effect
through positioning of the tongue (E1399) will be denied as
not reasonable and necessary. There is insufficient evidence
to show that these items are effective therapy for OSA.
A prefabricated OA (E0485) will be denied as not reason-
able and necessary. There is insufficient evidence to show
that these items are effective therapy for OSA.
Custom-fabricated mandibular advancement devices that
do not meet the requirements in the Coding Guidelines
section of the Related Policy Article (E1399) will be denied
as not reasonable and necessary.
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DaneshGroup.com

Summary of Practice Parameters for Surgical
Treatment of Obstructive Sleep Apnea in Adults
4.1 Diagnosis
4.1.1 The presence and severity of OSA must be determined
before initiating surgical therapy. (Standard)
4.1.2 The patient should be advised about potential surgi-
cal success rates and complications, availability of alternative
treatment options such as nasal PAP and oral appliances, and
the levels of effectiveness and success rates of these alterna-
tive treatments. (Standard)
4.2 Treatment objective: The desired outcomes of treat-
ment include resolution of the clinical signs and symptoms
of OSA and the normalization of sleep quality, the AHI, and
oxyhemoglobin levels. (Standard)
4.3 Surgical Procedures
4.3.1 Tracheostomy: Tracheostomy has been shown to be an
effective single intervention to treat OSA. This operation
should be considered only when other options do not exist,
have failed, are refused, or when this operation is deemed
necessary by clinical urgency. (Option)
4.3.2 Maxillomandibular advancement: MMA is indi-
cated for surgical treatment of severe OSA in patients who
cannot tolerate or are unwilling to adhere to PAP therapy, or
in whom oral appliances, which are often more appropriate
in mild and moderate OSA patients, have been considered
and found ineffective or undesirable. (Option)
4.3.3 Uvulopalatopharyngoplasty as a single surgical pro-
cedure: UPPP as a sole procedure, with or without tonsil-
lectomy, does not reliably normalize the AHI when treating
moderate to severe OSA. Therefore, patients with severe
OSA should initially be offered PAP therapy, while those
AHI = apnea-hypopnea index; LAUP = laser-assisted uvuloplasty; MMA = maxillomandibular advancement; MLS = multilevel or stepwise surgery;
OSA = obstructive sleep apnea; PAP = positive airway pressure; RFA = radiofrequency ablation; UPPP = uvulopalatopharyngoplasty.
From Aurora RN, Casey KR, Kristo D, et al: Practice parameters for the surgical modifications of the upper airway for obstructive sleep apnea in adults.
Sleep 2010;33:14081413.
Appendix 20-3
with moderate OSA should initially be offered either PAP
therapy or oral appliances. (Option)
4.3.4 Multilevel or stepwise surgery. Use of MLS, as a
combined procedure or stepwise operations, is acceptable in
patients with narrowing of multiple sites in the upper airway,
particularly if they have failed UPPP as a sole treatment.
(Option)
4.3.5 Laser-assisted uvulopalatoplasy: LAUP is not rou-
tinely recommended as a treatment for OSA syndrome.
(Standard)
4.3.6 Radiofrequency ablation: RFA can be considered as
a treatment in patients with mild to moderate OSA who
cannot tolerate or who are unwilling to adhere to PAP, or in
whom oral appliances have been considered and have been
found ineffective or undesirable.
4.3.7 Palatal implants: Palatal implants may be effective in
some patients with mild OSA who cannot tolerate or are
unwilling to adhere to PAP therapy, or in whom oral appli-
ances have been considered and found ineffective or unde-
sirable. (Option)
5.0 Follow-up
Postoperatively after an appropriate period of healing,
patients should undergo follow-up evaluation including an
objective measure of the presence and severity of sleep-
disordered breathing and oxygen saturation, as well as clini-
cal assessment for residual symptoms. In addition, patients
should be followed over time to detect recurrent of disease.
(Standard)
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Central Sleep Apnea and
Hypoventilation Syndromes
Chapter Points
Hypocapnic CSA occurs because the PaCO2 falls below
the AT. The propensity for this type of central
apnea to occur is increased when there is a small
difference between the sleeping PaCO2 during sleep
and the AT.
Hypocapnic CSA disorders include primary CSA
(idiopathic CSA), CSB-CSA, HAPB, and some types of
CompSA.
Hypocapnic CSA is often less severe during REM sleep
because this sleep stage is associated with lower
ventilatory responses to PaCO2 and PaO2, and
ventilation varies with the phasic changes of this sleep
stage.
CompSA is defined as the persistence or emergence of
central apneas during a PAP titration in a patient with
predominantly obstructive or mixed respiratory events
during the diagnostic portion.
CompSA can occur in patients with a combination of
OSA and CSB, patients taking opiates, or patients
without an obvious etiology (idiopathic).
CompSA patients without CSB or opiate medication
usually experience a resolution of CSA with chronic
CPAP treatment. Patients with persistent CSA on CPAP
require adaptive servo-ventilation or BPAP with a
backup rate for effective treatment.
Hypercapnic CSA syndromes are characterized by
sleep-related hypoventilation with variable amounts of
CSA. Some patients may have a normal daytime PaCO2.
The CCHS is a rare disorder usually present from birth
and is characterized by alveolar hypoventilation
without evidence of lung, neuromuscular, or structural
brainstem abnormalities. The disorder is due to
mutations in the PHOX2b gene.
Opiate (narcotic)-associated sleep-disordered
breathing can be manifested by long obstructive
apneas, a slow respiratory rate, ataxic breathing,
periodic breathing-central apneas or CompSA. Some
patients have daytime hypoventilation.
Chapter 21
Patients with RTCD or NMD may manifest daytime
hypoventilation that worsens during sleep or exhibit
hypoventilation only during sleep early in the disease
course. Although classified under the hypercapnic CSA
subgroup, many patients have relatively few discrete
central apneas.
In RTCD/NMD patients, nocturnal gas exchange is
usually the most abnormal during REM sleep.
Nocturnal oximetry may reveal significant
desaturation even if the forced vital capacity is
not severely reduced. If OSA is suspected PSG is
indicated.
The treatment of choice for CSA/nocturnal
hypoventilation in RTCD/NMD patients is NPPV.
In RTCD/NMD patients a daytime PaCO2 45 mm Hg
or nocturnal oximetry showing 5 minutes with an
SaO2 88% is considered an indication for nocturnal
NPPV.
In patients with an NMD, an FVC < 50% of predicted or
a maximal inspiratory force less than 60 cm H2O is also
considered an indication for NPPV.
Patients with restrictive chest wall disorders may
require relatively high pressure support.
Most clinicians would treat RTCD/NMD patients with
BPAP using a backup rate (BPAP-ST).
The central sleep apnea (CSA) syndromes include a diverse
group of disorders associated with the presence of central
apnea during sleep (Fig. 211).13 In some of the disorders
discussed in this chapter, the patients have primarily noctur-
nal hypoventilation (increased arterial partial pressure of
carbon dioxide [PaCO2]) due to inadequate tidal volume
and/or respiratory rate with relatively few discrete central
apneas. However, discussion of patients with central apnea
and hypoventilation syndromes together is useful clinically
because they have many similar aspects of pathophysiology
and treatment.
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376 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes

FIGURE 211 A central sleep apnea event in a patient

with the idiopathic central sleep apnea syndrome (primary
central sleep apnea). Note that the central apnea followed a
large breath. EMG = electromyogram; SpO2 = pulse C4-M1
oximetry. Adapted from Berry RB: Sleep Medicine Pearls, 2nd
ed. Philadelphia: Hanley & Belfus, 2003, p. 237. O2-M1

E1-M2

E2-M2

Chin EMG

Airflow
(nasal
pressure)

Chest

Abdomen

SpO2 96% 1 sec

Cflow

Chest

Abdomen

SpO2
180 seconds

FIGURE 212 Cheyne-Stokes breathing with central hypopnea at the nadir of ventilatory effort. This patient had obstructive and mixed apneas during the
diagnostic portion of a sleep study. When placed on continuous positive airway pressure (CPAP), the underlying ventilatory instability was uncovered. Here,
Cflow is the signal from the accurate flow transducer in the positive airway pressure (PAP) device. SpO2 = pulse oximetry.

Central apnea in adults is defined as a cessation in airflow
of 10 seconds or longer that is associated with an absence
of respiratory effort.4 During diagnostic studies oronasal
thermal sensor signal is used to detect apnea. During a posi-
tive airway pressure (PAP) titration the PAP flow signal is
used. The diagnosis of a CSA syndrome requires that the
majority of apneic events be central in nature. The exact
proportion of central events required is not clear, with
various authors diagnosing the CSA syndromes when 50%
to 80% of the events are central. Traditionally, patients with
CSA have accounted for less than 5% to 15% of patients with
sleep apnea evaluated at most sleep centers. However, two
factors have increased the number of CSA patients being
evaluated. First, there has been an increased recognition of
sleep-disordered breathing in congestive heart failure (CHF)
and a substantial number of patients with systolic heart
failure have Cheyne-Stokes breathing central sleep apnea
(CSB-CSA) (Fig. 212). Second, recently, there has been
more aggressive use of opiates to control pain. As discussed
in this chapter, many patients develop central apnea as a
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 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 377

FIGURE 213 Central, obstructive, and mixed

hypopneas. In central hypopnea, the flow falls in
Central Hypopnea proportion to the respiratory effort. The airflow profile
using an accurate measure of airflow (including nasal
Airflow pressure or CPAP flow) shows a round contour. In
(PTN) obstructive hypopnea, there is evidence of airflow
limitation (flat airflow shape) and flow falls even
though respiratory effort stays the same or increases.
In mixed hypopnea, there is a fall in respiratory effort
Esophageal
pressure
but the fall in flow is proportionately greater and there
is evidence of airflow limitation. Adapted from Berry
RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley
& Belfus, 2003, p. 83.
Obstructive Hypopnea
Airflow
(PTN)

Esophageal
pressure b b

Mixed Hypopnea

Airflow
(PTN)

Esophageal
pressure
PTN  pneumotachograph

result of the use of potent narcotics. Central apnea may occur
either at baseline or once patients are exposed to PAP treat-
ment. Thus, sleep centers can expect to see more patients
with CSA.
Many patients who exhibit central apneas also exhibit
central hypopneas (see Fig. 212). The challenges in defining
central hypopnea were discussed in earlier chapters. The
American Academy of Sleep Medicine (AASM) scoring
manual discourages identification of central hypopnea unless
an accurate method to quantify respiratory effort is being
used (esophageal pressure or respiratory inductance plethys-
mography).4 In general, central hypopneas are characterized
by a proportionate decrease in both airflow and respiratory
effort (Fig. 213).5 Usually, there is no snoring or chest-
abdominal paradox and the nasal pressure or PAP device
flow signal is fairly rounded (minimal or no signs of airflow
limitation).
CLASSIFICATION OF CSA SYNDROMES
There is a number of classifications of CSA and the hypoven-
tilation syndrome but none of these classifications is entirely
satisfactory.1,6 The International Classification of Sleep Dis-
orders, 2nd edition (ICSD-2) lists five CSA syndromes (Box
BOX 211
Central Sleep Apnea Syndromes
1. Primary central sleep apnea
2. Cheyne-Stokes breathing pattern
3. High-altitude periodic breathing
4. Central sleep apnea due to drug or substance
5. Primary sleep apnea of infancy
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
211).6 Primary CSA is termed idiopathic central sleep apnea
(ICSA) in this chapter, in keeping with much of the literature.
Primary CSA, CSB-CSA, and high-altitude periodic breath-
ing (HAPB) are hypocapnic forms of CSA. Patients with
these syndromes have a normal or low PaCO2 during wake-
fulness. During sleep, these patients do not develop hyper-
capnia. In contrast, patients with CSA due to drug or
substance and primary sleep apnea of infancy have normal
or increased daytime PaCO2 and may develop or have
worsening hypercapnia during sleep. The ICSD-2 lists five
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378 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
BOX 212
Hypoventilation Syndromes
1. Sleep-related nonobstructive alveolar hypoventilation,
idiopathic
Comment: Rare, usually case reports
2. Congenital central alveolar hypoventilation syndrome
Example: Central congenital hypoventilation syndrome
3. Sleep-related hypoventilation due to medical condition
A. Sleep-related hypoventilaton/hypoxemia due to
lower airways obstruction
Examples: Hypercapnic COPD, bronchiectasis, or
cystic fibrosis
B. Sleep-related hypoxemia due to pulmonary
parenchymal or vascular pathology
Example: Sleep-related hypoventilation with
idiopathic pulmonary fibrosis or other interstitial lung
diseases or pulmonary vascular disease associated
with end-stage lung disease
C. Sleep-related hypoventilation/hypoxemia due to
neuromuscular and chest wall disorders
Examples: Obesity hypoventilation syndrome,
neuromuscular disease, kyphoscoliosis
See Appendix 211 for diagnostic criteria.
COPD = chronic obstructive pulmonary disease.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
American Academy of Sleep Medicine. Westchester, IL: American Academy of
Sleep Medicine, 2005.
categories of hypoventilation syndromes (Box 212). Idio-
pathic nonobstructive hypoventilation is due to an abnor-
mality of ventilatory control of unknown etiology. Congenital
hypoventilation syndrome is due to abnormal ventilatory
control due to a genetic abnormality. Three groups of disor-
ders with hypoxemia or hypercapnia during sleep are listed.
The first is due to lower airways obstruction (e.g., chronic
obstructive pulmonary disease), the second is due to pulmo-
nary parenchymal or vascular disorders (e.g., pulmonary
fibrosis, interstitial lung disease), and the third is due to
abnormality of the chest wall or neuromuscular disorders
(e.g., kyphoscoliosis, amyotrophic lateral sclerosis [ALS],
obesity hypoventilation syndrome [OHS]). Patients with the
OHS are discussed in Chapter 15. The effects of chronic
obstructive pulmonary disease on sleep (including hyper-
capnia) are discussed in Chapter 22.
This chapter utilizes a classification of the CSA syndromes
adapted from one proposed by Bradley and coworkers1 (Box
213) that subdivides patients into hypocapnic and hyper-
capnic groups. Patients with hypocapnic CSA tend to have
low to normal daytime PaCO2 values. The disorders in this
group include ICSA, CSB-CSA, HAPB, and treatment-
persistent/-emergent CSA.
The term complex sleep apnea (CompSA) has been used
to identify patients who have primarily obstructive or mixed
events during diagnostic studies but develop central apneas
on PAP treatment (treatment-emergent central apneas) or
BOX 213
Central Sleep Apnea Syndromes
HYPOCAPNIC (normal or low daytime PCO2)
1. Idiopathic central sleep apnea
2. Cheyne-Stokes breathingcentral sleep apnea
Associated with congestive heart failure
Associated with neurologic disease
3. Periodic breathing at high altitude
4. Complex sleep apnea (treatment emergent or persistent
sleep apnea)
Idiopathic complex sleep apnea*
Combined OSA and CSB (CPAP eliminates obstruction
and unmasks CSBCSA)
HYPERCAPNIC
1. Wont breathe
A. Central hypoventilation
Congenital central hypoventilation syndrome
Idiopathic central hypoventilation syndrome
Brain tumors, cerebrovascular disease
Structural brain disordersChiaris syndrome
Apnea of infancy
B. Medication-induced central sleep apnea (narcotics/
opiates)
Central sleep apnea with normal or increased
daytime PCO2
Complex sleep apnea (treatment emergent or
persistent central sleep apnea)
C. Obesity hypoventilation syndrome
2. Cant Breathe
A. Restrictive thoracic cage disorders
B. Neuromuscular disorders
i. Motor neuron disease including poliomyelitis
ii. Neuropathy
iii. Neuromuscular junction disorders (myasthenia
gravis)
iv. Myopathy (muscular dystrophy)
*Idiopathic complex sleep apnea refers to patients with CompSA who do not
have Cheyne-Stokes breathing or are not taking narcotics or other
medications altering ventilatory drive.
Some patients with these disorders may have normal daytime PaCO2.
CompSA = complex sleep apnea; CPAP = continuous positive airway
pressure; CSA = central sleep apnea; CSB = Cheyne-Stokes breathing; OSA =
obstructive sleep apnea; PaCO2 = arterial partial pressure of carbon dioxide;
PCO2 = partial pressure of carbon dioxide.
have significant persistent central apneas on PAP treatment
(treatment-persistent central sleep apnea).7 It is not unusual
for patients with obstructive sleep apnea (OSA; predomi-
nantly obstructive apneas and hypopneas) to have some
mixed or central apneas during diagnostic studies.8,9 PAP
will eliminate central and mixed as well as obstructive apneas
in many of these patients on the first treatment night (or
during the initial PAP treatment).9 In other patients, central
apneas will persist after airway obstruction is eliminated. In
the early studies of the effect of treatment of OSA patients
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 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 379

30 seconds

Airflow

Chest

Abdomen

SaO2
88%

FIGURE 214 A mixed apnea. Note the crescendo-decrescendo pattern of ventilatory effort. When the patient was placed on CPAP, the mixed apneas were
converted to central apneas of the Cheyne-Stokes type. Another hint that the patient has congestive heart failure is the delay in the arterial oxygen saturation
(SaO2) nadir. The 88% occurs before the termination of the event pictured. In fact, this desaturation is not due to the event pictured but to the previous event.
Airflow = nasal pressure. From Malhotra A, Berry RB, White DP: Central sleep apnea. In Carney P, Berry RB, Geyer JW (eds): Clinical Sleep Medicine. Philadelphia:
Lippincott Williams & Wilkins, 2005, p. 341.

with tracheostomy (elimination of obstruction), patients
were found to have residual central apneas that tended to
resolve with chronic treatment.8 The term CompSA is also
sometimes used to include patients with narcotic-associated
sleep-disordered breathing who have persistent or emergent
central apneas on PAP. Patients with this condition usually
have high normal or mildly increased PaCO2 during wake-
fulness. In this chapter, this group is discussed under the
hypercapnic CSA group. It is also not uncommon for patients
with CHF to have a combination of obstructive or mixed
apnea and CSB-CSA (Fig. 214).10 In some of these patients,
application of PAP will eliminate obstruction but frequent
central apneas of the Cheyne-Stokes type may persist or
emerge. For this reason, the term CompSA is sometimes
applied. These patients are discussed with the nonhypercap-
nic CSA disorders. Patients with CompSA without an
obvious etiology (no narcotics or heart failure) are termed
idiopathic CompSA for lack of a better terminology. These
patients have an instability in ventilatory control either at
baseline or due to PAP treatment. Because they have normal
or low daytime PaCO2, they are discussed in the hypocapnic
CSA sections.
The hypercapnic CSA syndromes associated with
hypoventilation include those with a defect in ventilatory
control (congenital central alveolar hypoventilation, acquired
central alveolar hypoventilation, CSA due to medication/
substance), patients with the OHS, thoracic cage disorders,
and neuromuscular disorders. The hypercapnic CSA group
can be divided into a wont breathe group (can reduce their
PaCO2 with voluntary increases in ventilation) and a cant
breathe group due to an abnormal thoracic cage or neuro-
muscular weakness. This classification is not entirely satis-
factory because patients with OHS have various combinations
of OSA, abnormal ventilatory control, and respiratory pump
abnormality (mass loading due to obesity). Of note, early in
the disease course, some patients with chronic hypoventi-
lation syndromes will have an increased PaCO2 only
during sleep. They may present with complaints of disturbed
sleep or nocturnal dyspnea, morning headaches, daytime
sleepiness, or insomnia. Later in the disease course, these
may present with hypercapnic respiratory failure and cor
pulmonale.
PATHOPHYSIOLOGY OF CSA
Effects of Normal Physiologic Changes
In normal individuals, there is a 2 to 8 mm Hg rise in PaCO2
during nonrapid eye movement (NREM) sleep. This is
thought due to loss of the wakefulness drive, reduction of the
hypercapnic and hypoxic ventilatory drives, and increased
upper airway resistance (Table 211).11 The wakefulness
drive is a poorly understood generalized augmentation of
ventilation associated with the wakefulness state. During
NREM sleep, ventilation is totally under metabolic control
(chemoreceptors). Ventilatory control centers respond to
information from the peripheral chemoreceptors including
the carotid body (arterial partial pressure of oxygen [PaO2]
and PaCO2) and medullary chemoreceptors (H+ due to
changes in PaCO2).11 During rapid eye movement (REM)
sleep, ventilation is irregular and nonmetabolic factors also
affect ventilation. The hypercapnic and hypoxic ventilatory
drives are lower during REM than during NREM sleep. In
addition, during REM sleep, there is generalized skeletal
muscle hypotonia.1113 The contribution of accessory muscles
of ventilation is either reduced or absent and ventilation
depends entirely on the diaphragm. The loss of accessory
inspiratory muscles can compromise the ability to maintain
adequate ventilation, especially in patients with muscle
weakness or a high work of breathing. During the phasic
changes of REM sleep (associated with bursts of eye
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380 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes

TABLE 211
Effect of Sleep on Ventilatory Control
WAKE NREM REM
Wakefulness drive Present Absent Absent
+
Central chemoreceptors (H , PCO2) Intact Reduced Very reduced
+
Peripheral chemoreceptors (PO2, PCO2 [H ]) Intact Reduced Very reduced
Apneic threshold Not present Present N/A
Behavioral and other nonventilatory Present Absent Periods of reduced tidal volume during phasic REM
control center influences sleep often associated with bursts of eye movements
N/A = not applicable; NREM = non-rapid eye movement; PCO2 = partial pressure of carbon dioxide; PO2 = partial pressure of oxygen; REM = rapid eye movement.

C4-M1
O2-M1

E1-M2
E2-M2

Chin EMG

Airflow
(nasal pressure)

Esophageal 20 cm H2O
pressure

FIGURE 215 Respiration during rapid eye movement (REM) sleep. Periods of diminished diaphragmatic activity (reflected in decreased
esophageal pressure excursions) and tidal volume associated with the phasic changes of REM sleep (associated with bursts of eye
movements). EMG = electromyogram. From Berry RB: Sleep Medicine Pearls, 2nd ed. Philadelphia: Hanley & Belfus, 2003, p. 31.

movements), there is often additional inhibition of upper TABLE 212

airway muscles and diaphragmatic activity resulting in epi- Mechanisms Inducing Central Apnea
sodes of central apnea or reduced tidal volume (Fig. 21
IDIOPATHIC CENTRAL
5).12,13 Patients with hypercapnic CSA/hypoventilation
SLEEP APNEA CHEYNE-STOKES BREATHING
syndromes usually have worse oxygenation and highest
PaCO2 during REM sleep. It is of interest that some patients High hypercapnic High hypercapnic ventilatory
with hypocapnic CSA due to ventilatory control instability ventilatory drive response (high controller gain)
(high controller gain) High sympathetic activity
may actually have better oxygen saturation during REM than
Small sleeping Pulmonary congestionhigh
during NREM sleep. For example, in the ICSA or CSB-CSA
PCO2AT difference PCWP (J receptor stimulation)
syndromes, central apneas generally do not occur during Sleep state instability Delay in arterial blood reaching
REM sleep. Some patients with CompSA will also have a (arousals) chemoreceptors
much better response to CPAP during REM sleep than Small sleeping PCO2AT
during NREM sleep. difference
AT = apneic threshold; PCO2 = partial pressure of carbon dioxide; PCWP =
pulmonary capillary wedge pressure.
Ventilatory Control in Hypocapnic CSA
A number of factors contribute to the occurrence of hypo-
capnic CSA (Table 212). Patients with hypocapnic CSA control model standpoint, they have high system loop gain
have a normal or low daytime PaCO2 and high ventilatory and ventilatory instability.16,17 Central apneas are more
responses to hypercapnia. They develop central apnea common in stage N1 and N2 rather than stage N3 sleep
because the PaCO2 falls below the apneic threshold (AT) to because ventilation is less stable on transition from wakeful-
be discussed in the following section.14,15 From a ventilatory ness to sleep. Sleep stage changes and arousal predispose to
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 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 381

Decreased Recovery
PETCO2
50

PETCO2 mmHg
40
30
20
10
0
10 sec
Tidal volume

0.8
0.6
(liters)

0.4
0.2
0
Recovery

Prehyperventilation Hyperventilation

FIGURE 216 Determination of the apneic threshold (AT). The subject undergoes positive-pressure ventilation until the end-tidal partial pressure of
carbon dioxide (PETCO2) drops and the ventilator is turned off. If PETCO2 is below the AT, central apnea ensues. From Skatrud JB, Dempsey JA: Interaction of
sleep state and chemical stimuli in sustaining rhythmic ventilation. J Appl Physiol 1983;55:813822.

the occurrence of central apneas in patients with hypocapnic 30

CSA.18 Hypocapnic central apneas are uncommon during
REM sleep because ventilation is not totally under metabolic 25
control and the ventilatory response to hypercapnia is lower
20
than during NREM sleep, making ventilatory instability less
Apnea duration, sec

likely. Short central apneas can occur during REM sleep 15

during bursts of eye movements but these are likely not due
to a lowering of PaCO2 below the AT. 10

Apneic Threshold
During wakefulness, hypocapnia does not cause cessation of
breathing due to the presence of the wakefulness stimulus to
breathing. During NREM sleep, ventilation depends com-
pletely on metabolic control. If the PaCO2 falls below a char-
acteristic value (AT) for each individual, a central apnea
occurs14,15 (Fig. 216). Ventilation does not resume until the
PaCO2 climbs above (and actually slightly higher than) the
AT. The AT can be experimentally determined by serial runs
of hyperventilation with positive-pressure ventilation that
progressively drop the PaCO2 to various levels below the
eucapnic PaCO2 level during sleep. The positive-pressure
ventilation is terminated suddenly, and if the PaCO2 has
dropped below the AT, a central apnea occurs. For example,
suppose the spontaneous sleeping PaCO2 is 42 mm Hg, then
trials could progressively induce PaCO2 values of 41, 40, 39,
38, 37, and so on. The level at which a central apnea occurs
when the positive-pressure device is turned off is the AT. As
noted previously, the sleeping PaCO2 is normally about 2 to
8 mm Hg above waking value. The typical AT is usually at
or 1 to 2 mm Hg lower than the waking PaCO2. In Figure
217, during normoxia, an individual end-tidal partial pres-
sure of carbon dioxide (PETCO2) increases with sleep from
40 to 44 mm Hg. Hyperventilation trials with positive-
pressure ventilation resulted in central apnea (apnea dura-
tion > 0 sec) in a range of PETCO2 values from about 38 to
42 mm Hg.
5
0
Spontaneous eupnea
32 34 36 38 40 42 44 46
PETCO2, mmHg
FIGURE 217 The results of determination of the apneic threshold (AT) in an individual
who spontaneously increases the end-tidal partial pressure of carbon dioxide (PETCO2)
from slightly above 40 mm Hg when awake to 44 mm Hg during sleep (spontaneous
eupnea shown by arrow). The AT varied but was usually at or slightly below the awake
arterial carbon dioxide pressure (PaCO2) value. PETCO2 values from 38 mm Hg to slightly
above 40 mm Hg resulted in central apnea (apnea duration > 0 sec). Note that there
was some variability with one trial resulting in a PETCO2 of 38 mm Hg that did not result
in central apnea. From Skatrud JB, Dempsey JA: Interaction of sleep state and chemical
stimuli in sustaining rhythmic ventilation. J Appl Physiol 1983;55:813822.
Of note, it is the difference between the sleeping PaCO2
and the AT rather than the position of the AT that is the
critical determinant of the propensity to develop central
apnea. The smaller the PaCO2-AT difference the more likely
CSA is to occur. Figure 218 shows awake and sleeping
PaCO2 values for CHF patients with and without periodic
breathing. Those with periodic breathing have a small differ-
ence between the sleeping PaCO2 and the AT. This is because
the PaCO2 increased relatively little with transition from
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382 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes

FIGURE 218 The awake eupnea end-tidal partial pressure of carbon

45
dioxide (PaCO2), sleeping PETCO2, and apneic threshold (AT) for patients with
congestive heart failure (CHF) with and without periodic breathing. The
patients with periodic breathing had a small sleeping PETCO2AT difference.
From Xie A, Skatrud JG, Puelo DS, et al: Apnea-hypopnea threshold for 40 *

PETCO2, mmHg
CO2 in patients with congestive heart failure. Am Respir Crit Care Med
2002;165:12451250.
35  

30

25
Awake Sleep Apnea Awake Sleep Apnea
eupnea eupnea threshold eupnea eupnea threshold
CHF CHF 
periodic breathing

wake to sleep but the AT did not show a corresponding Controller gain
decrease.19

VE
Studies have shown that the PaCO2-AT difference can
vary with changes in ventilatory drive.20 Specifically, the PCO2 Response
PaCO2-AT difference increases with the induction of meta-
Circulatory delay (VE)R
bolic acidosis (acetazolamide) and decreases with metabolic VE
alkalosis. This is somewhat counterintuitive because one Plant gain
PCO2
might expect that further increases in ventilatory drive due

PCO2
to metabolic acidosis would increase the propensity for
central apnea. In contrast to metabolic acidosis, hypocapnic
hypoxia decreases the PaCO2-AT difference. Thus, hypox- VE
emia can increase the likelihood of central apnea. A detailed Disturbance
description of the factors that affect the PaCO2-AT difference
is found in references 15 and 20. (VE)D

Loop Gain Loop gain (LG)  plant gain  controller gain

Ventilatory control stability has also been analyzed using
feedback control theory focusing on the loop gain (LG) of
the respiratory system.2,16,17 The LG is determined by the
plant gain (ability of increases in ventilation by the lungs/
respiratory muscles to reduce the PaCO2) and the controller
gain (change in ventilation induced by a change in PaCO2)
(Fig. 219). High plant gain ( PaCO2/ ventilation) is asso-
ciated with hypercapnia and low physiologic dead space.
Owing to the hyperbolic relationship between ventilation
and PaCO2, small changes in ventilation induce larger
changes in PaCO2 if hypercapnia is present (Fig. 2110A).
Controller gain depends on the sensitivity of the ventilatory
control centers to changes in PaCO2. Controller gain can be
expressed as Ventilation/ PaCO2. The LG = plant gain
controller gain. A system with a high LG (LG > 1) is unstable
(see Fig. 2110B). High controller gain or high plant gain
can destabilize the system. In hypocapnic CSA, the major
factors causing instability are the high controller gain and
the effect of wake-to-sleep transitions.
Upper Airway and Posture Effects
Both ICSA and CSB-CSA tend to be worse in the supine
position.21,22 In ICSA patients, Issa and Sullivan21 found
FIGURE 219 The interaction between controller gain and plant gain for the
respiratory system. High controller gain or high plant gain results in a large response to
a small disturbance (change in ventilation). D = disturbance; PCO2 = partial pressure of
carbon dioxide; R = response; VE = volume of expired gas. From White DP: Central sleep
apnea. In Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine.
Philadelphia: Elsevier, 2005, pp. 969981.
central apnea to be more frequent in the supine position.
They hypothesized that upper airway reflexes may trigger
central apnea because upper airway anesthesia abolished
central apnea in two patients. In addition, high levels of
continuous positive airway pressure (CPAP) abolished
central apnea. CSB-CSA has also been noted to be more
prominent in the supine position.22 It is not known whether
this is due to upper airway factors or to changes in oxygen-
ation or pulmonary congestion.
HYPOCAPNIC CSA SYNDROMES
Patterns of Ventilation in ICSA and CSB
The patterns of ventilation differ between patients with
CSB-CSA and patients with ICSA. In both groups, the
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 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 383

12 FIGURE 2110 A, Starting at a lower arterial partial pressure

of carbon dioxide (PaCO2) means that to induce a given change
10 in partial pressure of carbon dioxide (PCO2) requires a large
Alveolar ventilation (L/min)

Starting at a lower PaCO2 requires

more change in ventilation change in ventilation (smaller plant gain). B, A system with a
8 for the same change in PCO2 loop gain (LG) of 1 or greater is unstable and tends to oscillate
after a disturbance. A and B, From White DP: Pathogenesis of
6 obstructive and central sleep apnea. Am J Respir Crit Care Med
2005;172:13631370.
4

0
20 25 30 35 40 45 50 55
A PCO2 (torr)

Disturbance Response
Disturbance
A: LG  0.5
Response

VT

Response Response
Disturbance
Disturbance Disturbance

B: LG  1

VT
B

TABLE 213
Differences in Respiration between Patients with Idiopathic Central Sleep Apnea and Cheyne-Stokes
Breathing
CENTRAL APNEA CYCLE VENTILATORY DELAY IN
DURATION (SEC) LENGTH (SEC) PHASE (BETWEEN APNEAS) (SEC) SaO2 NADIR (SEC)
ICSA 20.9 37.3 16.7 10.3
CSB-CSA (CHF) 22.3 59.0 36.7 24.3
CHF = congestive heart failure; CSA = central sleep apnea; CSB = Cheyne-Stokes breathing; ICSA = idiopathic central sleep apnea; SaO2 = arterial oxygen saturation.
From Hall MJ, Xie A, Rutherford R, Bradley TD: Cycle length of periodic breathing with and without heart failure. Am J Respir Crit Care Med 1996;154:376381.

central apneas typically are 20 to 40 seconds in duration. In
ICSA, there is typically a short ventilatory phase of 2 to 4
breaths between central apneas, and arousals tend to occur
at apnea termination (Fig. 2111). Patients with CSB have a
longer ventilatory phase between consecutive apneas, and
the ventilatory phase has a characteristic crescendo-
decrescendo morphology. Hall and colleagues23 compared
cycle length between patients with ICSA and CSB-CSA due
to heart failure (Table 213). The apnea durations were
similar but cycle length was longer in CSB-CSA due to a
long ventilatory phase. The CSA-CSB patients also had a
longer delay in the arterial oxygen saturation (SaO2) nadir.
The lower the cardiac output, the longer the ventilatory
phase and the delay in SaO2 nadir. This is believed due
to a long circulation time. The patterns of ventilation
in treatment-emergent CSA (nonhypercapnic, non-CSB
CompSA) resembles that of ICSA.
Idiopathic CSA (Primary CSA)
These patients have central apneas of unknown etiology.
CHF, neurologic disorders, or medications suppressing ven-
tilation are not present. The prevalence varies but is thought
to be 5% to 10% of patients being studied in sleep centers.
Patients may present with symptoms similar to those of
patients with OSA. These may include daytime sleepiness or
insomnia, snoring, witnessed breathing pauses, and dis-
turbed sleep. They tend to be thinner than patients with OSA
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384 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes

CSA-CSB has longer cycle length due to a longer ventilatory phase

Cheyne-Stokes breathing Idiopathic CSA

Cycle length Cycle length

Airflow
Airflow

Ventilatory phase Ventilatory phase

SaO2
SaO2

CSA-CSB often has arousal at the zenith of ventilatory effort and the nadir in the SaO2 is delayed

Cheyne-Stokes breathing Idiopathic CSA

A A
Airflow Airflow
B B
SaO2 SaO2

A  position of arousal
B  delay in saturation nadir

FIGURE 2111 Schematic illustrations of the difference between idiopathic central sleep apnea (CSA) and Cheyne-Stokes breathing
(CSB) central apnea associated with heart failure. The ventilatory phase is longer in CSB-CSA, arousal occurs at the zenith of ventilation,
and the nadir in the arterial oxygen saturation (SaO2) is delayed.

BOX 214 trigger a transient increase in ventilation and a fall in PaCO2.

Primary Central Sleep ApneaDiagnostic Criteria
A. The patient reports at least one of the following:
i. Excessive daytime sleepiness.
ii. Frequent arousals and awakenings during sleep or
insomnia complaints.
iii. Awakening short of breath.
B. Polysomnography shows five or more central apneas per
hour of sleep.
C. The disorder is not better explained by another current
sleep disorder, medical or neurologic disorder,
medication use, or substance use disorder.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
and have less prominent snoring. In the ICSD-2, the termi-
nology for this patient group is primary CSA (Box 214).
Pathophysiology of Idiopathic CSA
As reflected in the term idiopathic, the etiology of primary
CSA is unknown. However, the patients have ventilatory
instability due to a high hypercapnic ventilatory response24
or sleep state instability.18 These patients tend to have
decreased PaCO2 values during wakefulness. Often, central
apnea can be triggered by only one or two large breaths (see
Fig. 211). The periods of increased ventilation triggering
central apneas often are associated with arousal. Arousal may
This transient fall in PaCO2 is then associated with a central
apnea as the patient returns to sleep. As discussed previously,
in some patients with ICSA, central apnea occurs mainly in
the supine position.21 Studies have documented a response
to CPAP in some ICSA patients.21,25 In research studies, the
addition of dead space or inhalation of PaCO2 with the goal
of increasing and/or stabilizing the PaCO2 has been shown
to reduce central apnea in ICSA patients.26 However, these
interventions have not been tried for long-term treatment
nor are they practical.
Polysomnography
Sleep studies in patients with ICSA typically reveal frequent,
isolated central apneas or runs of central apneas (a form of
periodic breathing). A run of central apneas may follow
arousal from a nonrespiratory stimulus. Central apneas in
ICSA patients occur during NREM sleep, most commonly
in stage 1 or 2 sleep. Central apnea in these patients is much
less common during stage N3 and REM sleep. The percent-
age of total respiratory events that must be central is not well
defined but is usually taken as greater than 50%.
Treatment of ICSA
Because idiopathic CSA is rare, most treatment information
comes from small case series (no randomized, controlled
studies) and no long-term studies of the effectiveness of
any treatment have been published. There is no uniform
consensus about the best treatment for patients with
ICSA. This group is heterogeneous, and treatment must be
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 Chapter 21
BOX 215
Possible Treatments for Idiopathic Central
Sleep Apnea
CPAP
Hypnotics
Respiratory stimulants (acetazolamide)
Oxygen therapy??
CPAP = continuous positive airway pressure.
individualized (Box 215). Various respiratory stimulants
have been tried as treatments for idiopathic CSA, with vari-
able amounts of success.2729 The best evidence is for use of
acetazolamide (Diamox), which is a carbonic anhydrase
inhibitor. Acetazolamide induces a metabolic acidosis and
reduces the pH even if the PaCO2 also decreases slightly.
DeBacker and associates27 studied the effects of acetazol-
amide 250 mg 1 hour before sleep after 1 month of treatment
in ICSA patients. The apnea-hypopnea index (AHI) was
reduced by about 50% and symptoms improved, although
sleep efficiency was not significantly better.27
Another treatment approach is to decrease arousals and
promote stage N3 sleep where ventilation is more stable and
the PaCO2 likely slightly higher. Hypnotics including
triazolam and zolpidem have been tried.3032 A recent trial
of zolpidem 10 mg in ICSA was reported by Quadri and
coworkers.31 The central AHI decreased from 30 to 13.5/hr
and subjective sleepiness as measured by the Epworth Sleepi-
ness Scale improved (from 13 to 8). However, in some
patients, obstructive events increased with hypnotic treat-
ment. Of note, hypnotics are relatively contraindicated in
hypercapnic CSA.
As noted previously, CPAP also appears to be effective
treatment in some patients with ICSA.21,25 The mechanisms
by which CPAP works are unknown. Four possibilities are
that nasal CPAP minimizes overshoots in PaCO2 after
arousal, slightly increases the sleeping PaCO2 in patients who
are hypocapnic at baseline, prevents high upper airway resis-
tance from inducing arousals, or prevents significant nega-
tive upper airway pressure (which may trigger reflex central
apnea). Patients who snore or have central apnea mainly in
the supine position might be assumed to be the best candi-
dates for CPAP treatment. Of note, one case report found
that CPAP helped but bilevel positive airway pressure (BPAP)
worsened CSA.33 BPAP may destabilize the system by aug-
menting ventilation. No study evaluating the effect of adap-
tive servo-ventilation (ASV), a mode designed to stabilize
ventilation, in ICSA has been published but a trial of that
treatment might be reasonable. Supplemental oxygen has
been shown to improve CSA in patients with CSB.34,35
However, an evaluation of supplemental oxygen in ICSA
patients has not been published. Supplemental oxygen might
work by decreasing ventilatory instability by blunting the
hypercapnic ventilatory response. The hypercapnic ventila-
tory response is increased by hypoxia and decreased
by hyperoxia.
Central Sleep Apnea and Hypoventilation Syndromes 385
CSB WITH CSA
CSB occurs most commonly in patients with left ventricular
systolic dysfunction3638 but also can occur in patients with
diastolic CHF or neurologic disorders.39,40 The neurologic
disorders associated with CSB include a prior cerebrovascu-
lar accident (CVA) and neurodegenerative disorders. CSB
may be present in up to 30% of patients in the first few days
after stroke.39,41 Central apnea tends to resolve and is less
commonly seen in studies of patients studied several months
after stroke. OSA is the predominant form of sleep apnea
present in patients after CVA. Of interest, a recent study sug-
gested that a significant proportion of CSB-CSA in stroke
patients was due to occult cardiovascular disease.42 CSA-CSB
has also recently been reported in patients with heart failure
with normal systolic function (diastolic heart failure).40
CSB-CSA due to systolic CHF is probably the most
common cause of CSA seen today. Javaheri and colleagues36
found occult sleep-disordered breathing in 45% of a group
with stable heart failure and an ejection fraction less than
45% and CSA was common in the affected individuals. Mac-
Donald and associates37 studied a group of patients in stable
CHF with maximal modern medical management and found
61% to have some form of sleep-disordered breathing (31%
central apnea and 30% OSA). Oldenberg and coworkers38
studied 700 patients with CHF and found similar results. It
should be noted that many patients in these studies had
various amounts of both central and obstructive apneas.
Defining what percentage of events qualified the patient for
the central apnea group was somewhat arbitrary. In addition,
patients can vary in the percentage of central events over-
night43 or from night to night.44 In any case, the prevalence
of CSB-CSA is very high in patients with significant systolic
heart failure.
Patients with CSA-CSB may complain of the typical
symptoms of sleep apnea including disturbed sleep or
daytime sleepiness. However, in most studies, the majority
of patients do not complain of subjective excessive daytime
sleepiness. Thus, a high index of suspicion is needed to
suspect the presence of CSB. Nocturnal sleep complaints are
often assumed to be secondary to CHF rather than to
co-morbid sleep apnea. Despite the lack of subjective sleepi-
ness complaints in CSB-CSA patients, studies have docu-
mented improvement in sleep quality and objective daytime
sleepiness with successful treatment.45
Polysomnography in CSB-CSA
The crescendo-decrescendo morphology of CSB-CSA has
previously been discussed (see Figs. 212, 214, and 2111).
Another characteristic to appreciate is the long delay in the
nadir in the SaO2 tracing after event termination due to a
prolonged circulation time (low cardiac output) (Fig. 2112).
The distinctive pattern of CSB may not be recognized during
a diagnostic study in a patient who has both OSA and
underlying CSB.10 However, during a subsequent PAP
titration, pure CSB-CSA may emerge when upper airway
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386 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
Nasal
pressure
Oronasal
thermal airflow
Chest
Abdomen
SpO2
91
30 sec
FIGURE 2112 Cheyne-Stokes breathing with central apnea in a patient with systolic heart failure central apnea. Note the long delay in the nadir in the pulse oximetry (SpO2). The
tracing is 180 seconds and the vertical lines denote 30-second epochs.
obstruction is eliminated (Fig. 2113). The possibility of
underlying CSB should be considered if mixed apneas during
the diagnostic study have a long central component or if the
nadir in the SaO2 following obstructive event termination is
delayed. If central hypopneas rather than central apneas are
present, this may also make CSB more difficult to recognize.
As noted previously, central hypopneas rather than apneas
can occur at the nadirs in ventilatory effort (see Fig. 212).
The typical CSB cycle time is relatively long at 60 to 90
seconds and may be missed if a short time window is used
to monitor sleep during a PAP titration. Figure 2113 also
illustrates the typical cessation of CSB-CSA when a patient
transitions from NREM to REM sleep.
Pathophysiology of CSB-CSA
The factors contributing to CSB include high ventilatory
drive (high sympathetic tone, pulmonary congestion), long
circulation time, and a small difference between the sleeping
PaCO2 and the AT. Patients with CSB have low daytime
PaCO2 compared with CHF patients without CSB46,47 due to
increased ventilatory drive. High drive is thought to be due
to increased sympathetic tone and pulmonary congestion
stimulation of lung J receptors. In one study of patients with
CHF, the higher the pulmonary capillary wedge pressure, the
lower the awake PaCO2 (Fig. 2114A).48 In another study,
the higher the pulmonary capillary wedge pressure, the
higher the AHI (see Fig. 2114B).49 As noted previously,
CHF patients with CSB also have a small difference between
the sleeping PaCO2 and the AT.19
One might expect CHF patients with CSA to have lower
cardiac output or ejection fraction compared with those that
do not have periodic breathing. However, one study compar-
ing groups with CHF with and without CSB found the two
groups had similar ejection fractions but the CSB patients
96 94 91 96
46 sec
had a lower daytime PaCO2.47 Other studies have found
lower ejection fractions in patients with CSB.37 A study by
Sin and colleagues50 of 450 men and women with CHF iden-
tified risk factors for the presence of OSA and CSA. Risk
factors for CSA included male sex, atrial fibrillation, age
older than 60, and hypocapnia (PaCO2 < 38 mm Hg) during
wakefulness. Risk factors for OSA included a high body mass
index (BMI) in men and an increase in age in women. The
presence of CSB-CSA also has prognostic implications.
Studies have suggested that the presence of CSA in
patients with CHF is associated with a worse prognosis
(Fig. 2115).51,52
Treatment of CSB-CSA
CSB-CSA in patients with CHF may improve with improved
medical treatment of heart failure.53 Transplantation may
also cure CSB-CSA.54 A number of treatments have been
tried including aminophylline,55 acetazolamide,56 hypnot-
ics,57 oxygen,34,35,58,59 and PAP52,60,61 (Box 216). Neither ami-
nophylline (can increase arrhythmias) nor acetazolamide
has been widely used. One study found temazepam reduced
the arousal index without worsening oxygenation but the
amount of CSB was not improved.57 In contrast, a number
of studies of 1 to 3 months duration have documented
improvement with CPAP in a substantial number of patients
showing an improvement in sleep quality and ejection frac-
tion and reduced sympathetic activity.52,60,61 Titration of
CPAP in CSB-CSA patients differs from that in OSA
patients. On a given titration night, a pressure that eliminates
CSA cannot usually be found. Typically, pressure is increased
until obstructive events are eliminated and then increased
to 8 to 10 cm H2O (if pressure is not already above that
level). In some studies of CPAP treatment for CSB-CSA,
CPAP was started on an outpatient basis and increased
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C4-M1

O2-M1

E1-M2

E2-M2

Chin

ECG

Cflow
Chapter 21

CPAP 10 cmH2O

Chest

Abdomen

SpO2

Transition to REM sleep

FIGURE 2113 Note the presence of CSB-CSA on continuous positive airway pressure (CPAP). Also note the sudden cessation of CSB-CSA on transition to rapid eye movement (REM) sleep. Cflow = flow signal from the CPAP
device; ECG = electrocardiogram; SpO2 = pulse oximetry.
Central Sleep Apnea and Hypoventilation Syndromes
387

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388 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes

44 100

42 Non-CSR-CSA

Transplant free survival (%)

80

40
PaCO2 mmHg

60
CSR-CSA
38
40

36
20 P  .032
34
0
0 6 12 18 24 30 36 42 48 54 60
32
12 14 16 18 20 22 24 26 28 30 Time from randomization (months)
A PCWP (mmHg) FIGURE 2115 Transplant-free survival in CHF patients with CSR-CSA was significantly
worse than in those with Cheyne-Stokes respiration (CSR)-CSA independent of the use
70 of CPAP. From Sin DD, Fitzgerald F, Parker JD, et al: Risk factors for central and obstructive
r  0.47 sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care
60 P  .006 Med 1999;160:64.
Apnea-hypopnea index (no/hr)

50

40 BOX 216

30 Treatments for Cheyne-Stokes BreathingCentral

20
10
0 BPAP with backup rate (BPAP-ST)
0 10 20 30
B PCWP (mmHg)
FIGURE 2114 A, The higher the pulmonary capillary wedge pressure (PCWP), the
lower the daytime arterial partial pressure of carbon dioxide (PaCO2) in a group of
patients with congestive heart failure. B, The higher the PCWP, the higher the apnea-
hypopnea index (AHI; central events) in a patient with congestive heart failure and
CSB-CSA. A, From Lorenzi-Filho G, Azevedo ER, Parker JD, Bradley TD: Relationship of
carbon dioxide tension in arterial blood to pulmonary wedge pressure in heart failure. Eur
Respir J 2002;19:3740. B, From Solin P, Bergin P, Richardson M, et al: Influence of
pulmonary capillary wedge pressure on central apnea in heart failure. Circulation
1999;99:15741579.
slowly with a goal of 8 to 10 cm H2O commonly recom-
mended.62 One randomized trial of CPAP provided prelimi-
nary evidence of prolonged survival in patients with
CSB-CSA treated with CPAP.52 The ability of CPAP to
improve mortality was subsequently investigated by the
Canadian Continuous Positive Airway Pressure for Patients
with Central Sleep Apnea and Heart Failure (CANPAP) trial.
This large, multicenter, randomized, controlled trial com-
pared CPAP and standard treatment for patients with CHF
and CSB-CSA.62 Unfortunately, the trial failed to show a
survival benefit with CPAP treatment and there was a trend
for higher early mortality in the CPAP group. The results
of the study were disappointing, but analysis showed that
only about 50% of patients responded to CPAP (defined as
an AHI < 15/hr on a sleep study after 3 mo of treatment).
Sleep Apnea Associated with Heart Failure
Optimize medical management (lower PCWP)
Supplemental oxygen
CPAP (effective in ~4050%)
40
ASV
Transplant
Note: Theophylline and acetazolamide (case report) have been reported to
be effective but are not used in clinical practice.
ASV = adaptive servo-ventilation; BPAP = bilevel positive airway pressure;
CPAP = continuous positive airway pressure; PCWP = pulmonary capillary
wedge pressure; ST = spontaneous-timed mode.
The average level of CPAP over 3 months was around 9 cm
H2O. Of interest, Javaheri and associates63 during a single
night of titration also found that 57% of patients responded
to CPAP. Given that only about 50% of patients in the
CANPAP trial responded to CPAP (AHI < 15/hr), the results
are not surprising. An analysis of the subgroups responding
and not responding to CPAP64 showed improvement in sur-
vival and ejection fraction in responders compared with
controls (Fig. 2116). However, this was a post-hoc analysis
and the results, although encouraging, do not prove the
effectiveness of CPAP for unselected patients with CSB-CSA
due to CHF.
Because only about 50% of patients with CSB-CSA
improve with CPAP treatment, ASV was developed to stabi-
lize breathing in CSB-CSA patients. A study by Teschler and
coworkers65 compared CPAP, oxygen, BPAP with a backup
rate (BPAP-ST [spontaneous-timed mode]), and ASV each
used for a single night (Fig. 2117). This study showed a
modest improvement in the AHI with oxygen and CPAP.
BPAP-ST was more effective. ASV reduced the AHI to very
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 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 389

Central Apnea Index

100
60
*
Heart transplant-free survival (%)

80

60 40

Events/hr
40

20
20 CPAP-CSA-suppressed (5 events)
Control (26 events)
CPAP-CSA-unsuppressed (13 events)
0
A 0 3 6 12 18 24 30 36 42 48 54 60 0
Control Oxygen CPAP Bilevel ASV
vs Control P < .001 P < .001 P < .001 P < .001
Baseline
3 mo vs ASV P < .001 P < .001 P < .001 P = .02
P = .984
40 FIGURE 2117 Effectiveness in reducing the central apnea index by oxygen,
P < .001 P = .006 continuous positive airway pressure (CPAP), bilevel positive airway pressure (BPAP) with
35 P = .409 P < .001 P = .678 a backup rate, and adaptive servoventilation (ASV). ASV was the most successful at
lowering the central apnea index. The figure shows box plots: horizontal bar (median);
30
thick vertical bars (interquartile range); thin bars (range excluding outliers); dots
LVEF (%)

25 (outliers). From Teschler H, Dhring J, Wang YM, Berthon-Jones M: Adaptive pressure

support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure.
20 Am J Respir Crit Care Med 2001;164:614619.
15

0
Control CPAP-CSA- CPAP-CSA-
B suppressed unsuppressed
FIGURE 2116 Results from an analysis of the data from the Canadian Continuous
Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure
(CANPAP) study. A, The patients who responded to continuous positive airway pressure
(CPAP; *) had better survival than the controls or the nonresponders. CSA = central sleep
apnea. B, The responders had an improvement in the left ventricular ejection fraction
(LVEF). A and B, From Naughton M, Bernard D, Tam A, et al: Role of hyperventilation in
the pathogenesis of central sleep apnea in patients with congestive heart failure. Am Rev
Respir Dis 1993;148:330338.
most insurance carriers. Conversely, if a patient has pre-
dominantly CSB-CSA on the diagnostic study, one may
proceed directly with an ASV titration unless reimburse-
ment issues mandate an initial trial of CPAP. The Centers for
Medicare and Medicaid Services (http://www.cms.gov/mcd/
viewlcd.asp?lcd_id=5023&lcd_version=56&show=all) and
many insurance carriers no longer require an attempt at
CPAP if a patient meets criteria for CSA on the diagnostic
study. A PSG must demonstrate the effectiveness of BPAP-ST
or ASV for treatment of CSA.
CMS criteria for CSA include:

low levels typical of CPAP titrations in OSA patients. Another
study found BPAP-ST to improve breathing in CSB-CSA
patients.66 A number of studies have documented that ASV
is well tolerated and effective in CSB-CSA patients.45,67,68 In
general, sleep quality improves with ASV treatment and
some studies have shown an improvement in ejection frac-
tion.67 Details of the use of ASV are discussed in Chapter 19.
At the present time, a randomized trial of ASV is in progress
to determine whether this treatment can improve mortality
in patients with CHF and CSB-CSA.
If a patient with CHF has predominantly OSA on a diag-
nostic study, then a CPAP titration is certainly indicated. If
underlying CSB is suspected in a patient with predominantly
obstructive events, a CPAP titration would still be indicated
because a study must demonstrate that the patient has
CompSA (emergence of frequent central apneas on CPAP)
before a device with a backup rate (ASV) is reimbursed by
1. AHI 5/hr,
2. Central apneas/hypopneas > 50% of the total apneas
and hypopneas, and
3. Central apneas/hypopneas 5/hr, and
4. Symptoms of excessive daytime sleepiness or disrupted
sleep.
Of note, some clinicians would still order a titration with
CPAP (at least during the initial part of the titration). Failure
of CPAP would then trigger an ASV titration during the rest
of the study. A problem with this approach is that there may
be insufficient time for an optimal ASV titration.
In summary, while the best treatment for patients with
CSB-CSA remains controversial, most clinicians would use
ASV unless a patient has a satisfactory response to CPAP.
Of note, BPAP without a backup rate is unlikely to be effec-
tive if CPAP is not effective. Attempts to optimize treatment
of CHF are an essential component of treatment in patients
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390 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
with CSB-CSA associated with heart failure. In fact, opti-
mization of medical treatment of CHF should be the first
treatment intervention in patients with CSB-CSA due to
heart failure.
COMPLEX SLEEP APNEA
CompSA has been defined in many ways7,68,69 but the CMS
definition is one of the most widely used. CompSA is defined
as a form of CSA identified by the persistence or emergence
of central sleep apneas or hypopneas upon exposure to
CPAP or BPAP without a backup rate when obstructive
events have disappeared. These patients have predominantly
obstructive or mixed apneas during the diagnostic portion
of the study occurring 5/hr or more. With use of CPAP or
BPAP without a backup rate, they show a pattern of apneas
and hypopneas that meets the definition of CSA (see previ-
ous section).
CompSA includes patients with no obvious cause for
treatment-emergent central apneas (idiopathic) as well as
some patients with a combination of OSA and CSB-CSA or
medication-induced central sleep apnea. However, these last
two groups are discussed in separate sections due to their
unique features. This section discusses mainly the idio-
pathic CompSA group, which is composed of patients who
develop treatment-emergent CSA without an obvious cause.
Pathophysiology
Patients with CompSA are thought to have an instability in
ventilatory control or a sleep state instability.69 The underly-
ing instability is believed to be exacerbated by CPAP or
BPAP. CPAP or BPAP could result in a lower sleeping PaCO2
by decreasing upper airway resistance. CompSA patients
probably also have low ATs and difficulty reaching stable
sleep. Some studies show a male predominance.70,71
Incidence and Natural History
The incidence of CompSA varies between studies.7,7074 Java-
heri and colleagues72 published a large retrospective analysis
of 1286 patients with a diagnosis of OSA who underwent a
CPAP titration and 6.5% of the patients had treatment-
emergent CSA. These patients had the most severe OSA and
had a central apnea index (CAI) of 5/hr or greater at baseline.
Of the 84 patients with CompSA, 42 returned for a second
titration. In 33 patients (78%), CSA was eliminated by CPAP.
Of note, most patients in this study had diagnostic and titra-
tion sleep studies on separate nights (no split studies). In
split studies, rapid titration could predispose to CompSA.
Dernaika and associates73 reported on a population of 116
patients who met criteria for a split-night study. Twenty-
three (19.8%) had CSA during a CPAP titration. Fourteen of
these patients underwent chronic CPAP treatment. Repeat
PSG with CPAP was performed an average of 9 weeks
after treatment. Objective adherence was documented. CSA
resolved in 12 of the 14 (92%). Lehman and coworkers74
reported on 100 patients with a retrospective analysis; 13
subjects (13%) had CSA-CPAP. Risk factors included male
sex, cardiac disease, and CSA on baseline PSG.74 In a referral
sleep clinic setting, Morganthaler and colleagues7 found that
15% of 223 consecutive patients referred for a sleep study
had CompSA.
Thus, the incidence of CompSA will depend on the clini-
cal setting and whether patients taking opioids and those
with CSB are included. The published studies suggest that
CSA will resolve in a large proportion of patients with
chronic CPAP treatment or with ASV treatment if indi-
cated.70,74 However, if patients with CompSA do not have
improvement in control of sleep apnea, they tend to have
poor sleep quality and are at risk for poor adherence. In one
study, patients with CompSA had more mask issues and
more complaints of removal of the mask.74
Polysomnography
CompSA patients have primarily obstructive or mixed
apneas and obstructive hypopneas during the diagnostic
study (or diagnostic portion of a split study). A small number
of central apneas may also occur. During the PAP titration,
the AHI remains elevated due to persistence or emergence
of central apneas or hypopneas. Because central hypopneas
are not well defined, this can be a problem in identifying
these patients. Often, CPAP is titrated to very high pressures
in an attempt to control respiratory events. Of interest, CPAP
may be more effective in CompSA patients during REM
sleep or in the lateral body position. Often an effective level
of CPAP appears to have been found, only to have the patient
change to the supine position with a subsequent return of
frequent central apneas. Figures 2118 and 2119 show trac-
ings on CPAP of a typical CompSA patient. In REM sleep,
respiration on CPAP is relatively stable on CPAP of 10 cm
H2O (see Fig. 2118, top panel). In stage N2, periodic breath-
ing with central apneas and hypopneas developed on the
same level of CPAP (see Fig. 2118, bottom panel). Subse-
quently, the pressure was raised to 12 cm H2O without
benefit. After repeated arousals, the patient attained stage N3
and respiration on CPAP of 12 cm H2O stabilized (see Fig.
2119, top panel). However, after a subsequent arousal, the
periodic breathing returned (see Fig. 2119, bottom panel).
These tracings emphasize that patients with idiopathic
CompSA often are better controlled during REM sleep and,
if they can attain stage N3, respiration may stabilize.
Treatment of CompSA
The best treatment for CompSA remains controversial. In
the absence of CSB-CSA or opioids, it appears that a signifi-
cant portion will improve with chronic CPAP alone.72,73 The
only problem with watchful waiting is that if the AHI remains
high, sleep quality will be impaired and adherence may
decrease. Therefore, it is prudent to assess patients soon after
starting CPAP. Many CPAP devices provide the ability to
estimate residual events. It is also important to remember
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 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 391

100 V F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore
CFLOW
Chest
Abdomen
CPAP 10 stage R supine epoch 428
SpO2

Cpres
30 sec

100 V F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore
CFLOW
Chest
Abdomen

SpO2

Cpres
CPAP 10 stage N2 supine epoch 446

FIGURE 2118 A patient with complex sleep apnea (CompSA). Top, The patient is in stage R on continuous positive airway pressure (CPAP) of 10 cm H2O with stable breathing.
Cflow = flow from PAP device; Cpres = pressure from PAP device; ECG = electrocardiogram; SpO2 = pulse oximetry. Bottom, A few epochs later in stage N1 or N2 on the same pressure,
recurrent central apneas are noted.

that the patient is being treated, not the AHI. Therefore, if a
patient reports good sleep and objective adherence is good,
intervention may not be necessary if the residual AHI
remains mildly elevated (510/hr). If patients do not improve
or if the residual AHI is high, most clinicians would order a
titration with ASV. Studies have documented that ASV is
effective in the majority of CompSA patients.75,76 A higher
minimal amount of pressure support may be needed if there
is significant nocturnal hypoventilation. Another option
would be treatment with BPAP-ST (backup rate) if ASV is
not effective. In one study comparing BPAP-ST with ASV,
both reduced the central apnea index, although ASV was
slightly more effective.75 ASV may be able to treat CompSA
patients using lower average pressures and a decreased
number of machine-triggered breaths compared with BPAP-
ST. The main adjustment required during ASV titration is
titration of expiratory positive airway pressure (EPAP). In
general, the EPAP will need to be at or close to the level of
CPAP needed to prevent obstructive apnea. This is often the
pressure that was effective during supine REM sleep.
However, if high EPAP is needed, this means that a fairly
high inspiratory positive airway pressure (IPAP) is required
to provide a reasonable amount of pressure support (IPAP-
EPAP). As discussed in Chapter 19, an ASV device that
automatically adjusts the EPAP during the night (between
EPAPmin and EPAPmax) is now available from one manu-
facturer. This option could be useful in a pressure-intolerant
patient or in one in whom the ASV titration does not docu-
ment an effective EPAP setting.
HIGH-ALTITUDE PERIODIC BREATHING
The ICSD-2 diagnostic criteria for HAPB are listed in Box
217. Periodic breathing is actually a normal adaptation to
high altitude. Some individuals develop mainly central
hypopnea whereas others have frank central apnea.77 As in
all hypocapnic CSA syndromes, the disorder is worse in
NREM than in REM sleep.
HAPB occurs in nearly everyone at 7600 m and is associ-
ated with fragmented sleep (decreased stage N3) from arous-
als. There are repeated cycling periods of hyperpnea and
apnea/hypopnea (periodic breathing). Patients complain of
poor sleep quality or suffocation. There is no association
between HAPB and the other altitude syndromes including
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392 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes

F4-M1
100 V C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore
Cflow
Chest
Abdomen
CPAP 12 supine epoch 495
SpO2

Cpres
100 V
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore
Cflow
Chest
Abdomen

SpO2
CPAP 12 supine epoch 515
Cpres

FIGURE 2119 Top, The same patient in Figure 2118 attained stage N3 sleep and respiration stabilized on the same continuous positive airway pressure (CPAP) of 12 cm H2O.
Cflow = flow signal from the CPAP device; Cpres = delivered pressure by the CPAP device; ECG = electrocardiogram; SpO2 = pulse oximetry. Bottom, After an arousal, the pattern of
periodic breathing returned on the same level of CPAP.

BOX 217 Treatment

High-Altitude Periodic BreathingDiagnostic
Criteria
A. Recent ascent to altitude of at least 4000 m.
B. Polysomnography demonstrates recurrent central
apneas primarily during NREM sleep at a frequency of
> 5/hr. The cycle length should be 1234 sec.
Note: This is a normal adaptation to altitude. An AHI cutoff separating
normal and abnormal is not defined. Symptoms of recurrent awakenings
or fatigue may occur.
AHI = apnea-hypopnea index; NREM = nonrapid eye movement.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
American Academy of Sleep Medicine. Westchester, IL: American Academy of
Sleep Medicine, 2005.
high-altitude pulmonary edema, high-altitude cerebral
edema, and acute mountain sickness, although patients with
acute mountain sickness will usually have HAPB.
Pathophysiology
Hypoxemia at altitude increases ventilatory drive, and this
results in periodic breathing. Individuals with a high hyper-
capnic ventilatory drive are more likely to develop HAPB.
Most patients gradually adapt to altitude. Benzodiazepines
have been used for the sleep disturbance and acetazolamide
has been used for acute mountain sickness including sleep
disturbance. For an in-depth discussion of high-altitude
illness, the reader is referred to reference 77.
HYPERCAPNIC CSA AND
HYPOVENTILATION SYNDROMES NOT
DUE TO LUNG DISEASE
These disorders have in common sleep-related hypoventila-
tion with variable amounts of central apnea and a normal or
increased awake PaCO2. Recall that sleep-related hypoventi-
lation is defined as an increase in the PaCO2 10 mm Hg
compared to an awake value. Daytime hypoventilation is
defined as a PaCO2 45 mm Hg. In some patients, early in
the disease course only nocturnal hypoventilation is present
(see Box 213). This section does not discuss patients with
nocturnal hypoventilation due to lung disease (see Chapter
22). In patients with hypoventilation not primarily due to
lung disease, the etiology is either the control of ventilation
(wont breathe) or the respiratory pump (thoracic cage or
respiratory muscles) (cant breathe). The wont breath group
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 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 393

can, with voluntary effort, lower their PaCO2 values. The
hypercapnic CSA syndromes are classified in the ICSD-2
under the hypoventilation syndromes. The hypoventilation
syndromes included in the ICSD-2 are listed in Box 212.
Detailed diagnostic criteria are listed in Appendix 211. The
ICSD-2 classification of hypoventilation syndromes is not
completely satisfactory because the OHS is probably better
classified with OSA syndromes rather than with neuromus-
cular disorders and disorders of the thoracic cage. In addi-
tion, some causes of central hypoventilation (brain tumor)
are neither idiopathic nor congenital.
Mechanisms of Hypercapnic CSA
and/or Hypoventilation
The mechanisms of CSA and/or hypoventilation in the group
of patients with hypercapnic CSA include alterations in che-
moreceptors, central ventilatory control centers, central
nervous system (CNS) respiratory pattern generators, lesions
of CNS or spinal cord motor pathways (trauma, tumor),
motor neuron disease (ALS), dysfunction of motor nerves,
neuromuscular junction disorders (myasthenia gravis),
myopathies (muscular dystrophy), or disorders of the tho-
racic cage (Fig. 2120).
Evaluation of Patients with Suspected
Hypoventilation
The diagnosis of hypoventilation (daytime or nocturnal)
should be considered in all patients with the disorders listed
in Box 213 or Figure 2120 who complain of nocturnal
symptoms including insomnia, dyspnea, disturbed sleep, or
frequent awakenings. However, lack of symptoms does not
rule out hypoventilation. The development of right heart
failure should also trigger suspicion but is often a late sign
(Fig. 2121). A reduced daytime SaO2 (92%) or an elevated
serum HCO3 (possible compensation for chronic respiratory
acidosis) should also increase suspicion of hypoventilation.78
In patients with normal lungs (normal alveolar-arterial [A-a]
gradient), significant hypoventilation can be present and the
SaO2 remains in the low-normal range (Box 218). An arte-
rial blood gas with a PaCO2 of 45 mm Hg or greater during
the day is the most definite method to diagnose daytime
hypoventilation. Depending on the clinical setting, a careful
neurologic examination, pulmonary function testing, chest
radiography, CNS imaging (ventilatory control dysfunction
suspected), genetic testing (if congenital central hypoventila-
tion syndrome [CCHS] is a possibility), and PSG may be
useful.78 Early in the disease course, some patients have only

MECHANISMS OF HYPERCAPNIC CENTRAL SLEEP APNEA

AND/OR HYPOVENTILATION DURING SLEEP

NREM
Arousal Wakefulness
from sleep drive

Chemo-sensors
Medulla
Ventilatory Sedatives, narcotics,
Idiopathic central hypoventilation CO2 (H)
pattern alkalosis
brain tumor, CVA
generators Carotid body
(PO2, PCO2)
Polio Upper
motor neuron

Lower
ALS, polio, phrenic nerve injury motor neuron
Myasthenia gravis Neuromuscular
junction

Myopathy Muscle

Lungs/
Kyphoscoliosis
chest wall

Ventilation
PCO2, PO2

FIGURE 2120 Summary of mechanisms of hypercapnic central sleep apnea and/or hypoventilation during sleep. ALS =
amyotrophic lateral sclerosis; CVA = cerebrovascular accident; NREM = nonrapid eye movement; PCO2 = partial pressure of carbon
dioxide; PO2 = partial pressure of oxygen. From Malhotra A, Berry RB, White DP: Central sleep apnea. In Carney P, Berry RB, Geyer JW
(eds): Clinical Sleep Medicine. Philadelphia: Lippincott Williams & Wilkins, 2005, p. 338.
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394 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes

nocturnal hypoventilation (see Fig. 2121). An arterial blood

gas drawn immediately on awakening can confirm nocturnal
hypoventilation. Noninvasive methods such as PETCO2 mon-
itoring or transcutaneous carbon dioxide (TcPCO2) moni-
toring can also be used if their accuracy can be documented.
Figure 2122 shows PSG in a patient with muscular dystro-
phy with hypoventilation documented by PETCO2. Nocturnal
oximetry in patients with suspected hypoventilation may
detect unexpected arterial oxygen desaturation. Whereas
this does not document nocturnal hypoventilation, it would
indicate the need for further diagnostic and therapeutic
interventions. Further comments on diagnostic evaluation
are included in specific disorders.
BOX 218
Example of a Patient with Daytime
Hypoventilation Due to Neuromuscular Disease*
Room air arterial blood gas: pH 7.36; PCO2 60 mm Hg; PaO2
70 mm Hg, SaO2 = 93%
PAO2 = 150 60/0.8 = 150 75 = 75
A-a gradient = PAO2 PaO2 = 75 70 = 5 (Normal)
FEV1 1.5 L (50% of predicted)
FVC 2.0 L (52% of predicted)
FEV1/FVC 0.80
*See Chapter 10 for discussion or respiratory physiology and pulmonary
function testing.
A-a gradient = alveolar-arterial gradient; FEV1 = forced expiratory volume in
1 second; FVC = forced vital capacity; PAO2 = alveolar partial pressure of
oxygen; PaO2 = arterial partial pressure of oxygen; PCO2 = partial pressure of
carbon dioxide; SaO2 = arterial oxygen saturation.
Congenital Central Hypoventilation Syndrome
CCHS is a rare disorder affecting approximately 1 per
200,000 live births.79 CCHS is usually present from birth and
is characterized by alveolar hypoventilation without evi-
dence of lung, neuromuscular, or structural brainstem
abnormalities. During wakefulness, many patients have
normal ventilation, although ventilatory responses to hyper-
capnia or hypoxemia by the rebreathing method are absent
or blunted and a perception of dyspnea is absent. The most
severely affected CCHS patients also have hypoventilation
during wakefulness. Those patients with normal awake ven-
tilation do have peripheral chemoreceptor responses to
hypoxemia or hypercapnia.80 It has been hypothesized that
the central integration of chemoreceptor information rather
than the chemoreceptors themselves is the abnormality in
patients with CCHS. One study found that CCHS patients
did have intact arousal responses to hypercapnia.81 However,
such arousals do not reliably result in an appropriate ventila-
tory response and rapid reversal of hypoxemia.
During sleep, all CCHS patients have worsening of ven-
tilation with profound hypoventilation exhibited by normal
respiratory rates and diminished tidal volumes associated
with severe falls in the SaO2.79,82 The abnormalities are often
worse during NREM than REM sleep because the control of
breathing is entirely metabolic during NREM sleep. In any
case, the arousal responses are significantly impaired because
long periods of hypercapnic hypoxemia without arousal are
not unusual.
Other forms of autonomic dysregulation may be seen in
these patients. These abnormalities can include Hirschsprungs

Worse Respiratory failure

Findings of cor pulmonale

Severity of abnormalities and symptoms

Daytime symptoms

Abnormal daytime gas exchange

Symptoms of sleep disturbances

Sleep study disturbances

Abnormal gas exchange during sleep

Severity of alveolar hypoventilation Worse

FIGURE 2121 The severity of symptoms of alveolar hypoventilation are related to the degree of alveolar hypoventilation.
As hypoventilation increases in severity, symptoms increase from only abnormalities during sleep to daytime symptoms and
finally to symptoms of overt respiratory failure. In patients with reduced cardiopulmonary reserve from co-morbid conditions,
this relationship is shifted upward and to the left as shown by the dashed line. From American College of Chest Physicians:
Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD,
and nocturnal hypoventilationa consensus conference report. Chest 1999;116:530.
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 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 395

FIGURE 2122 A 30-second tracing of NREM sleep in

a patient with muscular dystrophy shows nocturnal
E1-M2 hypoventilation with minimal drop in the arterial
oxygen saturation (SaO2). ECG = electrocardiogram;
E2-M2
EMG = electromyogram; Exhaled PCO2 = partial
F4-M1 pressure of carbon dioxide (capnography tracing); HR =
C4-M1 heart rate; NP = nasal pressure; PETCO2 = end-tidal
O2-M1 partial pressure of carbon dioxide. From Wagner MH,
Chin EMG Berry RB: Disturbed sleep in a patient with Duchenne
ECG muscular dystrophy. J Clin Sleep Med 2008;4:173175.
HR

Snore

NP

Airflow

Chest

Abdomen

SaO2 90 90 90 89 90 90 90 91 92 91 92 93 93 94

PETCO2 54 54 56 54 56 54 55 54 54 53 56 56 57 53

Exhaled PCO2

disease (20%) usually presenting with constipation, esopha-
geal dysmotility presenting with feeding difficulty, tumors of
neural crest origin (6%) such as neuroblastoma or ganglio-
neuroma, decreased heart rate variability, decreased heart
rate response to exercise, decreased papillary light response,
intermittent profuse sweating, and dysregulation of body
temperature with decreased baseline body temperature.78,82,83
CCHS patients are at risk for adverse outcomes from respira-
tory infections because they may not exhibit a fever or com-
plain of dyspnea even if severely hypoxemic.
The diagnosis of CCHS should be considered if apneic
or cyanotic spells are noted in infants, especially if associ-
ated with sleep. The most severe cases occur in patients who
do not breathe adequately during wakefulness after birth
and require immediate ventilatory support. In others, the
abnormalities are noted when the infants sleep. Milder cases
may present later with signs of cor pulmonale or hypoxic
damage to CNS structures. Some cases may not present
until late childhood and a few present in adulthood.84,85 The
diagnosis of CCHS depends on exclusion of other causes
of hypoventilation such as brainstem malformation, inborn
errors of metabolism, myopathy, diaphragmatic paralysis,
lung or respiratory pump abnormalities. PSG with PETCO2
monitoring usually reveals high PETCO2 and low tidal
volume (Fig. 2123).82
A suspected diagnosis is confirmed by genetic testing for
mutations in the PHOX2b gene.79,82,86,87 Most persons with
CCHS are heterozygous for polyalanine repeat expansion
mutations in exon 3 of PHOX2b. The expansion results in
lengthening the normal 20-repeat polyalanine tract to 2533
repeats. Longer expansions are associated with more severe
phenotypes. Most mutations occur de novo, but in families
with CCHS, it is inherited as an autosomal dominant trait.
Treatment includes lifelong ventilatory support for all
patients during sleep. Some patients will require ventilatory
support while awake as well. Ventilatory support for severe
cases is usually provided by a volume-cycled ventilator via
a tracheostomy. In older and milder patients, noninvasive
mask ventilation may suffice.79,83,87 Diaphragmatic pacing has
also been used during the day. Diaphragmatic pacing at
night requires the presence of a tracheostomy, because
obstructive events usually occur when the upper airway
muscles do not contract in synchrony with the diaphragm.
Infants in CCHS must be closely monitored because they
are at risk for hypoventilation or apnea at sleep onset. These
children are also at increased risk during chest infections
owing to their abnormal temperature control, lack of per-
ception of dyspnea, and nonappearance of respiratory dis-
tress. Noninvasive positive-pressure ventilation (NPPV)
with BPAP with a backup rate has been successfully used
in infants when parents have refused tracheostomy.88,89
Appropriate alarms are essential. Older children may be
transitioned to NPPV if their symptoms are milder and
they are adherent to treatment.
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396 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes

C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
ECG
Nasal
pressure
Chest

Abdomen

SpO2

96 97 80 75

PETCO2
36 42 65 57

FIGURE 2123 Thirty-second tracings during wakefulness (left) and NREM sleep (right) in a patient with congenital central
hypoventilation syndrome. Right central and occipital electroencephalographic (C4-M1, O2-M1) and right and left electro-oculographic
derivations (E1-M2, E2-M2) as well as a chin electromyogram (EMG) tracing are shown. During sleep, there is a dramatic reduction in tidal
volume, increase in end-tidal partial pressure of carbon dioxide PETCO2, and decrease in pulse oximetry (SpO2). ECG = electrocardiogram.
From Wagner MH, Berry RB: A full term infant with cyanotic episodes. Congenital central hypoventilation syndrome. J Clin Sleep Med
2007;3:425426.

Other Neural Disorders Causing
Central Hypoventilation
CSA and hypoventilation due to abnormalities in the control
of ventilation have been noted in a wide variety of disorders
but most are relatively uncommon. These include idiopathic
central hypoventilation, neurodegenerative disorders with
autonomic dysfunction90 such as multiple system atrophy,
paraneoplastic encephalitis,91 and tumors of the medulla.92,93
CSA and OSA can occur late in the course in patients with
prior polio infection (postpolio syndrome).94 The Chiari syn-
drome is discussed in the next section.
Chiaris Malformation
Sleep-related breathing disorders are common in both chil-
dren and adults with Chiaris malformation (CM).95,96 With
the increased use of magnetic resonance imaging (MRI),
cases are often detected before symptoms begin. CM type I
is defined as herniation of the cerebellar tonsils through the
foramen magnum. CM II includes caudal displacement of
the vermis and is usually associated with myelodysplasia and
meningomyelocele. In CM I, obstructive apneas, central
apneas, or a combination can occur. Nocturnal hypoventila-
tion without discrete apneas can also occur. A minority of
CM I patients have daytime hypercapnia, but the disorder is
included in this section because central apnea is believed to
be secondary to alterations in brainstem control of respira-
tion. Presenting symptoms of CM include worsening of
snoring, breathing pauses, headaches, neck pain, ataxia, ocu-
lomotor disturbances, scoliosis, and lower cranial nerve
palsies. Although CM I can present in infancy and child-
hood, the most common presentation is in young adulthood
between 20 and 40 years. Sleep apnea is believed due to
pressure on the medullary structures controlling ventilation
and upper airway muscles. Surgical decompression (poste-
rior fossa decompression, duraplasty, and cervical laminec-
tomy) often improves the degree of sleep apnea, although
significant apnea can be present in the postoperative period.
There have been reports of patients treated for obstructive
hydrocephalus with shunts who experienced an acute wors-
ening of sleep apnea as the only manifestation of shunt
failure.
CSA Due to Medication (Opiate/Narcotic-Induced CSA)
The opiate-induced sleep-related breathing disorder
(OSRBD) is increasingly common with more aggressive
treatment of chronic pain with potent narcotics including
morphine, fentanyl, and methadone, often in very high
doses. Affected patients may manifest obstructive apneas
often of long duration, ataxic breathing, low sleeping respira-
tory rates, and central apneas either intermittent or in the
form of periodic breathing.97,98 They also tend to have either
persistent or treatment-emergent central apneas on CPAP (a
form of CompSA). The etiology of the disorder is believed
to be depression of central drive by opiate medications.
Although opiate-induced CSA is placed in the hypercapnic
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 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 397

CSA group, patients often have either normal or only mildly
increased daytime PaCO2 values (4550 mm Hg). However,
patients with OSRBD more often exhibit significant worsen-
ing of hypoventilation during sleep. The many breathing
abnormalities noted in OSRBDs are listed in Box 219. An
unusual characteristic noted during sleep studies is the ataxic
breathing patternvariation in tidal volume and respiratory
rate (Fig. 2124). Some patients actually have central apneas
during stage N3 sleep (uncommon in other types of central
sleep apnea) and others have a low respiratory rate during
sleep (see Fig. 2124) or periodic breathing with repetitive
central apneas that are typically short in duration (Fig.
BOX 219
Important Facts about Opiates and Sleep-Related
Breathing Disorders
Ataxic breathingvariation in respiratory rate and tidal
volume.
Slow respiratory rate during sleep.
Intermittent central apneas (even during stage N3) or
periodic breathing with central apneas.
Long obstructive apneas.
Relatively few arousals, amount of stage N3 can be
increased.
In some patients, NREM AHI REM AHI.
Treatment-emergent central apneas are common even if
diagnostic study shows mainly obstructive events.
AHI = apnea-hypopnea index; NREM = nonrapid eye movement; REM =
rapid eye movement.
2125). Individual patients may have long obstructive apneas
during REM sleep or mixed apneas with a long central com-
ponent. Patients may also exhibit relatively few central
apneas until placed on CPAP (Fig. 2126). As in CSB-CSA,
patients with opiates are often more effectively treated with
CPAP during REM sleep (Fig. 2127).
Treatment
Some patients will improve with a reduction in narcotic
dose,2 but this is rarely acceptable to the patient. Other
patients with mainly obstructive events may respond to
CPAP. However, central apneas either persist or emerge on
CPAP in a significant number of patients (see Figs. 2125
and 2126). There is a single case report of use of acetazol-
amide99 as an adjunct to CPAP treatment in patients with
narcotic-induced CompSA. Treatment with either BPAP
with a backup rate or ASV can be successful in narcotic-
induced CompSA.100102 Relatively few studies using ASV in
patients with opiate-induced CSA have been published. One
study found ASV less effective but the EPAP probably was
not adequately increased to eliminate obstruction.101 When
using ASV, it is essential to increase EPAP sufficiently to
prevent upper airway closure.100,102 Javaheri and associates102
found ASV to be an effective treatment for both central and
obstructive apnea in narcotic-induced CompSA.
Primary Sleep Apnea of Infancy
This syndrome was formerly termed primary sleep apnea of
the newborn. As the name implies, this syndrome is char-
acterized by CSA due to an immature respiratory control

F4-M1 F4-M1
C4-M1 C4-M1
O2-M1 O2-M1
E1-M2
E2-M2 E1-M2
Chin E2-M2
ECG Chin EMG
Snore
ECG
Nasal
pressure Snore

Oronasal
airflow Nasal
pressure
Chest
Chest
Abdomen
Abdomen
SpO2 SaO2
94%

30 sec 30 seconds

FIGURE 2124 Left, Low respiratory rate in a patient on methadone (67 breaths/min). A 60-second tracing is shown. Right, Variation in flow amplitude and rate (ataxic
DaneshGroup.com
breathing) in another patient on methadone. ECG = electrocardiogram; EMG = electromyogram; SaO2 = arterial oxygen saturation; SpO2 = pulse oximetry.
398 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes

100 V F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Nasal
pressure

No airflow

Chest

Abdomen

SpO2

FIGURE 2125 Periodic breathing during a diagnostic study in a patient on a fentanyl patch. Repeated central apneas are noted without any arousals. Respiratory events without
arousals is common in opiate-induced central sleep apnea. ECG = electrocardiogram; SpO2 = pulse oximetry.

100 V F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
HR
ECG
Snore
CFLOW
Chest
Abdomen

SpO2

Cpres

FIGURE 2126 Periodic breathing with central apneas on CPAP of 10 cm H2O during NREM sleep. The patient was taking methadone. Cflow = flow signal from the CPAP device;
Cpres = pressure from PAP device; ECG = electrocardiogram; HR = heart rate; SpO2 = pulse oximetry.

system.6,103 Periodic breathing is a normal finding in pre-
mature infants but is deemed pathologic only if the duration
of apnea is greater than 20 seconds or if the events are associ-
ated with desaturation or other physiologic compromise. The
disorder may be treated with caffeine or low-dose theophyl-
line104 (Box 2110).
Restrictive Thoracic Cage Disorders
Disorders causing restriction of the thoracic cage due to
disease of the spine, chest wall, or pleura can result in
hypoventilation. Causes include thoracoplasty, fibrothorax,
kyphoscoliosis, and ankylosing spondylitis.6,105 In general,
isolated nocturnal hypoventilation precedes daytime
hypoventilation. These disorders result in extrinsic restric-
tive ventilatory dysfunction78 (Fig. 2128). In patients with
chest wall disease, the total lung capacity is decreased and
the functional residual capacity is either normal to increased
(ankylosing spondylitis) or decreased (kyphoscoliosis).78 The
chest wall has decreased compliance, so there is an increased
work of breathing. Patients tend to take rapid shallow breaths.
The severity of impairment may be roughly gauged by the
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 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 399

F4-M1
100 V C4-M1
O2-M1
E1-M2
E2-M2
Chin
HR
ECG
Snore
Cflow
Chest
Abdomen
SpO2

Cpres
30 sec

FIGURE 2127 Good control of respiratory events with CPAP of 10 cm H2O during REM sleep in the patient with methadone-induced central apnea during NREM sleep shown in
Figure 21-26. Cflow = flow signal from the CPAP device; ECG = electrocardiogram; HR = heart rate; SpO2 = pulse oximetry.

BOX 2110 TLC

Primary Sleep Apnea of InfancyDiagnostic
Criteria
APNEA OF PREMATURITY
A. One of the following is recorded in an infant < 37 wk
conceptional age: FRC
1. Prolonged central respiratory pauses of 20 sec in
duration. RV
2. Shorter-duration events include obstructive or mixed
respiratory patterns and are associated with a
significant physiologic compromise, including
decrease in heart rate, hypoxemia, clinical symptoms,
or the need for nursing intervention. Normal Scoliosis Ankylosing Simple OHS Chronic
spondylitis obesity neuro-
APNEA OF INFANCY muscular
disorder
A. One of the following is recorded in an infant of
conceptual age 37 wk: FIGURE 2128 Changes in lung volumes in patients with extrinsic restrictive
1. Prolonged central respiratory pauses of 20 sec in ventilatory dysfunction. In patients with obesity, scoliosis, and the obesity hypo-
duration. ventilation syndrome (OHS), the functional residual capacity (FRC) is decreased. In
chronic neuromuscular disorders, both the total lung capacity (TLC) and the FRC are
2. Shorter duration events including obstructive or
reduced. In patients with neuromuscular disorders, the residual volume (RV) is usually
mixed respiratory patterns and are associated with
unchanged unless significant expiratory muscle weakness is present (quadriplegia).
bradycardia, cyanosis, pallor, or marked hypotonia.
From Berry RB, Sriram P: Evaluation of hypoventilation. Semin Respir Crit Care Med
B. For either diagnosis, the disorder is not better explained
2009;30:303314.
by another current sleep disorder, medical or neurologic
disorder, or medication.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. documenting 5 minutes or longer with an SaO2 of 88% or
American Academy of Sleep Medicine. Westchester, IL: American Academy of lower is considered an indication for nocturnal NPPV (Table
Sleep Medicine, 2005.
214).106 However, PSG is the most sensitive test to deter-
mine nocturnal hypoventilation and rule out coexistent
OSA. Hypoventilation is often inferred from documenting
arterial oxygen desaturation without discrete events. This
forced vital capacity (FVC). An FVC less than 50% of pre- practice has been discouraged by the AASM scoring manual.4
dicted is considered severe.106 However, patients with FVCs However, many sleep centers do not have the ability to
higher than 50% may hypoventilate and desaturate at night. monitor PaCO2 noninvasively. An arterial blood gas on
Nocturnal oximetry is a useful tool in this setting. A daytime awakening is one approach. The most severe desaturation
PaCO2 documenting hypoventilation or nocturnal oximetry usually occurs during REM sleep (Fig. 2129).
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400 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes
TABLE 214
Indications for Noninvasive Positive-Pressure
Ventilation Treatment in Restrictive Thoracic Chest
Wall Disease and Neuromuscular Disease
RTCD Symptoms of hypoventilation (morning headache,
daytime somnolence)
AND one of the following:
Physiologic criteria
PaCO2 > 45 mm Hg (daytime)
Nocturnal oximetry demonstrating SaO2 < 88%
for 5 min*
NMD Symptoms of hypoventilation (morning headache,
daytime somnolence)
AND one of the following:
Physiologic criteria
PaCO2 > 45 mm Hg (daytime)
Nocturnal oximetry demonstrating SaO2 < 88%
for 5 min*
FVC < 50% of predicted
Maximal inspiratory pressure < 60 cm H2O
*The ACCP conference used at least 5 consecutive minutes. However, the
Centers for Medicare and Medicaid Services indications for respiratory assist
devices does not include consecutive but only 5 min with an SaO2 88%.
FVC = forced vital capacity; NMD = neuromuscular disease; PaCO2 = arterial
partial pressure of carbon dioxide; SaO2 = arterial oxygen saturation; RTCD =
restrictive thoracic chest wall disease.
From American College of Chest Physicians: Clinical indications for
noninvasive positive pressure ventilation in chronic respiratory failure due to
restrictive lung disease, COPD, and nocturnal hypoventilationa consensus
conference report. Chest 1999;116:521534.
REM REM
TcPCO2 (mm Hg) SpO2 (mm Hg)
90
80
70
60
40
20
1 hour
FIGURE 2129 Trends in the pulse oximetry (SpO2) and transcutaneous partial
pressure of carbon dioxide (TcPCO2) during the night in a patient with neuromuscular
disease. Note the simultaneous increase in TcPCO2 and decrease in the SpO2 during
episodes of rapid eye movement (REM) sleep. PCO2 = partial pressure of carbon dioxide.
Treatment of Restrictive Thoracic Cage Disorders
Early intervention may prevent the onset of cor pulmonale
and improve sleep quality. Most clinicians would start
treatment after documentation of nocturnal desaturation
or hypoventilation. Nocturnal ventilatory support rather
than supplemental oxygen is the treatment of choice. A
number of studies have evaluated the use of NPPV in these
100
Theoretical
80
Vital capacity (% of predicted)
60
40
20
20 40 60 80 100
Respiratory muscle strength
(% of predicted)
FIGURE 2130 The vital capacity in patients with neuromuscular disease is decreased
out of proportion to the degree of muscle weakness. This implies a change in the chest
wall or lungs that decreases the respiratory system compliance. From De Troyer A,
Borenstein S, Cordier R: Analysis of lung volume restriction in patients with respiratory
muscle weakness. Thorax 1980;35:603610.
patients.107110 NPPV is usually provided using BPAP in the
ST mode with a mask interface. NPPV can be started on an
outpatient basis, but NPPV titration with PSG is the ideal
method to select appropriate treatment. Due to the low com-
pliance of the respiratory system, high pressure support
(IPAP-EPAP) up to 20 cm H2O may be needed to deliver an
adequate tidal volume. Some patients may be ventilated with
lower pressure support and higher than spontaneous respira-
tory rates. NPPV is discussed in more detail in Chapter 19.
Neuromuscular Weakness
Hypoventilation can occur with disorders that impair func-
tion at any point from premotor neuron to muscle. These
sites include disorders of the premotor neurons, neural path-
ways to lower motor neurons, peripheral nerve disorders,
disorders of the neuromuscular junction (myasthenia gravis),
or myopathies (muscular dystrophy).
These disorders result in extrinsic restrictive ventilatory
dysfunction. Later in the disease course, abnormalities of the
lung can also occur. Although it is often said that testing
respiratory muscle strength (maximum inspiratory force,
expiratory force) is the most sensitive method to detect
respiratory weakness, these tests require special expertise to
avoid erroneous measurements and normative values for
strength vary considerably.78 The FVC is a very useful mea-
surement in neuromuscular disease (NMD). Studies have
shown that the FVC is reduced out of proportion to the
degree of muscle weakness, making it a fairly sensitive means
of documenting the significance of suspected respiratory
muscle weakness111 (Fig. 2130). The American College of
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 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes 401

96 prevention of worsening of hypoventilation, and avoiding

cor pulmonale. A randomized study in ALS patients found
90
increased survival with NPPV in the group of patients with
less severe bulbar dysfunction.115 The average IPAP and
EPAP settings were 15 and 6 cm H2O, respectively. This and
Mean SpO2

84
other studies reported improvement in quality of life with
NPPV. Patients with bulbar involvement may have more dif-
78
ficulty tolerating NPPV and mask ventilation. These patients
may also have a greater risk of aspiration than those without
72
upper airway dysfunction.
66
0 10 20 40 50 60 70 80
CLINICAL REVIEW QUESTIONS
FVC (% predicted)
1. All of the following are true about CCHS EXCEPT
FIGURE 2131 The mean arterial oxygen saturation (SpO2) determined by nocturnal
oximetry is plotted against the forced vital capacity (FVC; % predicted) for a group of A. It is associated with Hirschsprungs disease.
patients with ALS. Note that many patients with an FVC greater than 50% of predicted B. It is due to mutations in the PHOX2b gene.
had substantial nocturnal desaturation (and presumably nocturnal hypoventilation). C. Hypoventilation is manifested by low tidal volume.
From Morgan RS, McNally S, Alexander M, et al: Use of sniff nasal inspiratory force to
predict survival in amyotrophic lateral sclerosis. Am J Respir Crit Care Med 2005;171:101. D. Patients develop dyspnea when hypoxic.
E. Patients may require 24-hour ventilatory support
from birth.

2. Which of the following does NOT predispose a patient to

Chest Physicians (ACCP) consensus guidelines106 recom- hypocapnic CSA?
mended an FVC less than 50% of predicted or a maximal
A. Large PCO2-AT gradient.
inspiratory pressure less than 60 cm H2O as indications for
NPPV treatment (see Table 214). However, this degree of B. Increased hypercapnic ventilatory drive.
FVC impairment is not sensitive for detection of nocturnal C. Frequent arousals.
desaturation (Fig. 2131). Therefore, nocturnal oximetry or D. NREM > REM sleep.
PSG is recommended if the patient complains of poor sleep E. Supine > nonsupine sleep.
quality, frequent awakenings, or nocturnal dyspnea. Of
interest, some patients with NMD cannot make a good 3. Which of the following patients with CSB-CSA likely has
mouth seal to allow estimate of inspiratory force. One study the lowest cardiac output and the longest delay in the
found using nasal inspiratory pressure was useful in assess- SaO2 nadir?
ing prognosis.112 Nocturnal oximetry showing more than 5
CYCLE LENGTH (START
minutes of continuous desaturation less than 88% is consid-
OF ONE CENTRAL APNEA APNEA
ered an indication for beginning NPPV treatment.106 Patients
PATIENT UNTIL THE NEXT) LENGTH
with NMD typically have the lowest SaO2 and high PaCO2
during REM sleep. A 40 20
B 75 25
Treatment of Nocturnal Hypoventilation Due to NMD C 50 25
In the past, volume ventilation via a tracheostomy was the D 50 20
usual mode of ventilatory support in NMD patients. Today,
NPPV using BPAP-ST with a mask interface is the most 4. A patient with suspected sleep apnea undergoes a split
widely used treatment.105,106,113115 NPPV can be started at low sleep study. During the diagnostic portion, the AHI is 50/
levels and increased based on nocturnal oximetry, daytime hr with 40 obstructive apneas, 10 mixed apneas, 0 central
PaCO2 measurements, or symptoms.114 For example, using apneas, and 30 hypopneas. During the CPAP titration on
BPAP-ST at 8/4 cm H2O with backup rate of 1 to 2 breaths/ CPAP of 10 cm H2O, obstructive apneas are abolished but
min below the spontaneous rate. A more precise approach is frequent central apneas of the Cheyne-Stokes type are
NPPV titration with PSG. Not all patients will tolerate an noted. The AHI on 10 cm H2O is 40/hr. Higher pressure
optimal degree of pressure support on the first night of treat- is no more effective. What do you recommend?
ment. BPAP with a backup rate is recommended because A. Optimize cardiac function.
patients may not consistently trigger IPAP-EPAP cycles due
B. Treatment with CPAP of 10 cm H2O.
to muscle weakness. NPPV treatment initiation is discussed
in more detail in Chapter 19. C. Titration with ASV.
The goals of NPPV treatment should be individualized D. A and B.
but include improved sleep quality and quality of life, E. A and C.
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402 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes

5. Which of the following is likely present in a patient with 2. A. A small PaCO2-AT gradient predisposes to hypocap-
CSB-CSA associated with heart failure? nic CSA.
A. High wedge pressure (left ventricular end-diastolic
pressure). 3. B. A longer ventilatory phase between events is associ-
B. Low hypercapnic ventilatory response. ated with a longer circulation time, lower cardiac output,
and a longer delay in the SaO2 nadir. The ventilatory
C. Daytime PaCO2 = 44 mm Hg.
phase = cycle length apnea duration = A (20 sec), B
D. Normal left atrial size. (50 sec), C (25 sec), D (30 sec).
6. A 50-year-old man undergoes a split sleep study. The
4. E. CSB may improve with improvement in cardiac func-
results are shown below. The central apneas were not of
tion. CPAP was not effective at reducing the AHI. The
the Cheyne-Stokes type. What do you recommend?
patient may receive some benefit from CPAP, which did
DIAGNOSTIC TITRATION eliminate OSA, but the residual AHI due to central apnea
Total sleep time (min) 120 150 is quite high. ASV can often reduce the AHI to less than
REM sleep (min) 10 40 5/hr. Whereas ASV is more effective at acutely reducing
AHI (#/hr) 50 22 the AHI, no direct long-term comparisons have been per-
Obstructive apneas (no.) 40 15 formed with CPAP treatment of patients with CSB-CSA.
However, short-term studies of ASV do report improve-
Central apneas (no.) 5 30
ment in symptoms and some report improvement in
Mixed apneas (no.) 5 0 cardiac function.
Hypopneas (no.) 40 10
5. A. Patients with CSB-CSA are more likely to have a large
REM AHI
left atrium, atrial fibrillation, a low daytime PCO2, and an
CPAP TST SLEEP AHI REM OA MA CA H
elevated wedge pressure.
6 15 0 40 0 10 0 0 0
7 15 0 40 0 5 0 0 5 6. B. The patient has treatment-emergent CSA. CPAP of
8 30 10 10 30 0 0 0 5 9 cm H2O was effective at eliminating obstructive events.
9 30 20 0 0 0 0 0 0 Higher pressure was associated with central apneas. In
10 30 10 10 0 0 0 5 0 other patients, treatment-emergent central apneas may
occur on pressures needed to prevent obstructive apneas
11 30 10 40 0 0 0 20 0
during REM sleep. The treatment-emergent central
A. CPAP of 8 cm H2O. apneas may resolve with chronic CPAP treatment (espe-
B. CPAP of 9 cm H2O. cially if the patient does not have CSB or is taking potent
C. CPAP of 10 cm H2O. narcotics).
D. ASV titration.
E. BPAP-ST titration. 7. D. The patient may have nocturnal hypoventilation, and
NPPV rather than supplemental oxygen is indicated for
7. A patient with a progressive neuromuscular disorder treatment of nocturnal hypoventilation. Some clinicians
reports mild snoring and has a daytime PaCO2 of would begin empirical BPAP 8/4 cm H2O with upward
42 mm Hg. However, nocturnal oximetry reveals an titration as indicated. However, a diagnostic PSG is indi-
SaO2 88% for 15 min. The FVC is 60% of predicted and cated to determine if OSA, nocturnal hypoventilation, or
the maximum inspiratory force is 70 cm H2O. What do both are present. If the nocturnal arterial oxygen desatu-
you recommend? ration is due to OSA alone, one might consider treatment
A. Nocturnal supplemental oxygen. with CPAP. However, given the likely need for NPPV in
the future, treatment with BPAP rather than CPAP is
B. Diagnostic PSG and PSG for titration with CPAP.
probably the best answer. A titration with NPPV (BPAP-
C. Diagnostic PSG and PSG for titration with BPAP. ST) can eliminate OSA events and treat nocturnal
D. Diagnostic PSG and PSG for titration with hypoventilation as well as provide respiratory muscle
BPAP-ST. rest. BPAP with a backup rate is recommended for
E. Empirical treatment with BPAP-ST 8/4 cm H2O and patients with neuromuscular disorders because they may
backup rate of 12 breaths/min. not trigger IPAP/EPAP cycles due to weak muscles (espe-
cially during REM sleep). A backup rate will also provide
Answers intervention for central apneas. Of note, a saw-tooth
pattern in the oximetry tracings used to screen a neuro-
1. D. Patients with CCHS do not experience dyspnea when muscular disorder patient for abnormal nocturnal gas
hypoxemic and are at risk from death due to respiratory exchange would suggest that sleep apnea is present (dis-
infections. crete events).
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 Chapter 21
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Sleep-Related Hypoventilation Syndromes
Diagnostic Criteria
1. Sleep-Related Nonobstructive Alveolar Hypoventilation,
Idiopathic
A. Polysomnographic monitoring demonstrates episodes
of shallow breathing longer than 10 seconds in dura-
tion associated with arterial oxygen desaturation and
frequent arousals from sleep associated with the
breathing disturbances or brady-tachycardia.
Note: Although symptoms are not mandatory to make
this diagnosis, patients often report excessive daytime
sleepiness, frequent arousals and awakenings during
sleep, or insomnia complaints.
B. No primary lung diseases, skeletal malformations, or
peripheral neuromuscular disorders that affect venti-
lation are present.
C. The disorder is not better explained by another
current sleep disorder, medical or neurologic disor-
der, mental disorder, medication use, or substance
use disorder.
Key features: No obvious cause such as a medical dis-
order or structural problems with the lung or chest
wall. These patients do not have a congenital form of
alveolar hypoventilation. However, late-onset con-
genital central hypoventilation has been described.
2. Congenital Central Alveolar Hypoventilation Syndrome
A. The patient exhibits shallow breathing, or cyanosis
and apnea, of perinatal onset during sleep.
Note: In severely affected infants, consequences of
hypoxia, including pulmonary hypertension and cor
pulmonale, may also be present.
B. Hypoventilation is worse during sleep than during
wakefulness.
C. The rebreathing ventilatory response to hypoxia and
hypercapnia is absent or diminished.
D. Polysomnographic monitoring during sleep demon-
strates severe hypercapnia and hypoxia predominantly
without apnea.
E. The disorder is not explained by another current sleep
disorder, medical or neurologic disorder, medication
use, or substance use disorder.
3. Sleep-Related Hypoventilation Due to Medical
Condition
I. Sleep-Related Hypoventilaton/Hypoxemia Due to
Lower Airways Obstruction
Appendix 211
A. Lower airways obstructive disease is present (as
evidenced by a forced expiratory volume exhaled
in one second/forced vital capacity ratio less
than 70% on pulmonary function testing) and is
believed to be the primary cause of hypoxemia.
B. Polysomnography or sleeping arterial blood
gas determination shows at least one of the
following:
i. An SpO2, during sleep of less than 90% for
more than 5 minutes with a nadir of at least
85%.
ii. More than 30% of total sleep time with an
SpO2 of less than 90%.
iii. Sleeping arterial blood gas with PaCO2 that
is abnormally high or disproportionately in-
creased relative to levels during wakefulness.
C. The disorder is not better explained by another
current sleep disorder, another medical or neuro-
logic disorder, medication use, or substance use
disorder.
II. Sleep-Related Hypoxemia Due to Pulmonary Paren-
chymal or Vascular Pathology
A. Lung parenchymal disease or pulmonary vascular
disease is present and believed to be the primary
cause of hypoxemia.
B. Polysomnography or sleeping arterial blood
gas determination shows at least one of the
following:
i. An SpO2 during sleep of less than 90% for
more than 5 minutes with a nadir of at least
85%.
ii. More than 30% of total sleep time at an SpO2
of less than 90.
iii. Sleeping arterial blood gas with PaCO2 that
is abnormally high or disproportionately
increased relative to levels during wakeful-
ness.
C. The disorder is not better explained by another
current sleep disorder, another medical or neuro-
logic disorder, medication use, or substance use
disorder.
III. Sleep-Related Hypoventilation/Hypoxemia Due to
Neuromuscular and Chest Wall Disorders
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408 Chapter 21 Central Sleep Apnea and Hypoventilation Syndromes

A. A neuromuscular or chest wall disorder is present
and believed to be the primary cause of
hypoventilation/hypoxemia.
B. Polysomnography or sleeping arterial blood gas
determination shows at least one of the following:
i. An SpO2 during sleep of less than 90% for
more than 5 minutes with a nadir of at least
85%.
ii. More than 30% of the total sleep time at an
SpO2 of less than 90%.
iii. Sleeping arterial blood gas with PaCO2 that
is abnormally high or disproportionately in-
creased relative to levels during wakefulness.
C. The disorder is not better explained by another
current sleep disorder, another medical or neuro-
logic disorder, medication use, or substance use
disorder.
Examples: Obesity hypoventilation syndrome,
neuromuscular disease, kyphoscoliosis.

PaCO2 = arterial partial pressure of carbon dioxide; SpO2 = pulse oximetry.

From American Academy of Sleep Medicine: ICSD-2 International Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. American
Academy of Sleep Medicine. Westchester, IL: American Academy of Sleep Medicine, 2005.
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Sleep and Obstructive
Lung Disease
Chapter Points
Patients with COPD may experience NOD without
discrete apneas and hypopneas.
In COPD, the NOD is worse during REM sleep.
NOD during REM sleep is often characterized by long
periods of irregular and reduced tidal volume.
A saw-tooth pattern on a nocturnal oximetry tracing in
a COPD patient suggests the possibility of coexisting
sleep apnea.
If the awake SaO2 is low, even the normal fall in PO2
with sleep will result in greater desaturation (drop in
SaO2) due to the initial position on the steep portion
of the oxyhemoglobin dissociation curve.
Mechanisms of NOD in COPD patients include a low
baseline SaO2 as well as hypopneic breathing during
REM sleep characterized by a low tidal volume
(hypoventilation) and a reduction in the FRC (greater
  mismatch).
V/Q
Nocturnal oxygen supplementation has not been
proven to improve sleep quality in patients with COPD.
Long-term oxygen treatment (24 hr/day) improves
survival in COPD patients with daytime hypoxemia
(PaO2 55 mm Hg, SaO2 88% OR PaO2 5559 mm Hg
and evidence of cor pulmonale; see Box 22-2).
The benefit of nocturnal oxygen supplementation in
patients with a daytime PaO2 60 mm Hg is unproven.
However, nocturnal supplemental oxygen is usually
provided if significant nocturnal hypoxemia is
documented (>5 min with SaO2 88%; see Box 22-2).
Poor sleep quality in COPD patients is believed due to
medication side effects, nocturnal cough, and dyspnea.
Bronchodilator therapy improves nocturnal gas
exchange in COPD, but only a few studies have
documented an improvement in sleep quality. If
bronchodilators are used, medications with a long
duration of action are preferred.
Benzodiazepine receptor agonists can be used with
caution to treat insomnia in stable COPD patients
without hypercapnic respiratory failure. A melatonin
receptor agonist (ramelteon) was demonstrated not to
worsen gas exchange and did improve sleep quality in
Chapter 22
one study. Sedating antidepressants are another
option, but their efficacy as a hypnotic in COPD
patients is unproven.
Patients with a combination of COPD and OSA (OLS)
often require treatment with a combination of PAP and
supplemental oxygen. Bronchodilator therapy may
improve nocturnal gas exchange and smoking
cessation should be encouraged.
BPAP may be better tolerated than CPAP in some
patients with the combination of COPD and OSA.
Nocturnal oxygen therapy in hypercapnic COPD
patients without OSA generally results in only mild
increases in the PaCO2. A greater increase in nocturnal
PaCO2 may occur in patients with a combination of
OSA and COPD when supplemental oxygen is
administered.
Studies suggest that OLS patients on long-term
oxygen therapy have better outcomes if OSA is
effectively treated with PAP.
Patients with nocturnal asthma experience a greater
than normal fall in the FEV1 (morning dippers). This can
be documented by peak flow measurements at
bedtime and on awakening.
Frequent awakening from nocturnal asthma is one of
the defining characteristics of moderate to severe
asthma. The presence of nocturnal asthma symptoms
means asthma is suboptimally controlled.
An inhaled corticosteroid is the first step in treating
patients with nocturnal asthma. The next option is
addition of a long-acting inhaled beta agonist.
OBSTRUCTIVE VENTILATORY DYSFUNCTION
Obstructive ventilatory dysfunction (OVD) describes a
pattern of pulmonary dysfunction characterized by a reduced
ratio of the forced expiratory volume in 1 second (FEV1) to
the forced vital capacity (FVC) on spirometry. In addition to
the reduced FEV1/FVC ratio there is a reduction in flow
manifested by a reduction in the FEV1 (Fig. 221).14 Patients
with very mild OVD may have a normal FEV1 but a reduced
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410 Chapter 22 Sleep and Obstructive Lung Disease

FEV1/FVC ratio. For convenience, the lower limit of normal patients. For example, using 90% of predicted as the lower
for the FEV1 is assumed to be 80% of predicted and the lower limit of normal for the FEV1/FVC ratio may be more sensitive
limit of normal for the FEV1/FVC ratio is assumed to be 0.70. for identification of OVD. Patients with OVD have normal
However, using a slightly higher value of the FEV1/FVC ratio or increased lung volumes (residual volume [RV], function
for the lower limit of normal is appropriate in younger residual capacity [FRC], and total lung capacity [TLC]) (Fig.
222). The first lung volume to be affected is the RV. Most
Lung volume here is RV
patients with OVD have an elevated RV due to airtrapping
from small airway narrowing and closure. With more severe
6 disease, the FRC and then the TLC may also be increased
(hyperinflation). However, the relative increase in the RV is
5 Expiration
greater than any increase in the FRC or TLC. In moderate
FEV1 FVC to severe OVD, the increase in RV is large enough (compared
4
Volume (liters)

with any increase in the TLC) to cause a reduction in the

3
FVC (see Fig. 222). The increase in the FRC and TLC is due
to loss of lung elastic recoil (emphysema) or airway disease
2 (asthma).
A significant acute response to inhaled bronchodilator is
1 defined by a 12% or greater increase in the FEV1 or FVC with
Inspiration Lung volume here is TLC a minimum of 200 mL absolute increase. Lack of an acute
0 bronchodilator response does not rule out a benefit from
0 1 2 3 4 5 6
chronic bronchodilator therapy.
A Time (seconds)
The common OVD disorders are listed in Table 221.
These include asthma (bronchospasm = reversible airway
6
obstruction), chronic bronchitis (productive cough/sputum
Normal
Mild OVD production usually with OVD), and emphysema (destruc-
5 tion of alveoli and increased size of terminal airspaces).
Patients often have a mixture of these manifestations and are
4 said to have chronic obstructive pulmonary disease (COPD).
Volume (liters)

Patients with asthma may have normal pulmonary function

3 between exacerbations that can occur after upper respiratory
Severe OVD tract infections, exposure to allergens, or exercise. They typi-
2
cally demonstrate a large improvement in the FEV1 or FVC
1
after inhaled bronchodilator. Asthmatics have bronchial
hyperresponsiveness to methacholine challenge (>20% fall
0 in FEV1 after inhaling low concentrations), allergen, or exer-
0 1 2 3 4 5 6 cise challenge (>20% fall in FEV1 after exercise). A diagnosis
B Time (seconds) of asthma can be made in a patient with normal pulmonary
FIGURE 221 A, Spirometry is the exhaled volume per time. B, Patterns of patients function by demonstration of bronchial hyperresponsive-
with mild and severe obstructive ventilatory dysfunction (OVD). The hallmark of ness. Some asthma patients have persistent airflow obstruc-
obstruction is a reduced forced expiratory volume in 1 secondtoforced vital capacity tion and require inhaled or even oral corticosteroids
(FEV1/FVC) ratio. RV = residual volume; TLC = total lung capacity. for improvement. Patients with severe asthma can have

FIGURE 222 Lung volumes including total lung capacity (TLC), Moderate
functional residual capacity (FRC), and residual volume (RV). In to severe
TLC Normal Mild
obstructive ventilatory dysfunction (OVD), the RV increases more than OVD
TLC OVD
the FRC and TLC. In moderate to severe OVD, the RV increase may be
enough to decrease the vital capacity (VC). ERV = expiratory reserve VC IC
volume; IC = inspiratory capacity; Vt = tidal volume. VC
Vt
FRC VC
VC
ERV
RV

0
RV

RV  residual volume
FRC  function residual capacity
TLC  total lung capacity
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 Chapter 22 Sleep and Obstructive Lung Disease 411

TABLE 221
Spectrum of Obstructive Ventilatory Dysfunction
DIFFUSING BRONCHODILATOR AIRTRAPPING AND
DIAGNOSIS CAPACITY RESPONSE HYPERINFLATION
Asthma Reversible airflow obstruction Normal Yes >12% often 25% May be present
(physiologic diagnosis)
Chronic bronchitis Productive sputum for 3 mo for 2 Normal Sometimes 1015% Air trapping (high
consecutive yr (clinical diagnosis) RV)
Emphysema Destruction of gas-exchanging units Decreased Rarely Yes
and enlargement of terminal
airspaces (pathologic diagnosis)
Mixed chronic bronchitis Combination Decreased None or small Yes
and emphysema (COPD)
In OVD the increase in RV > increase in FRC > increase in TLC.
Air trapping manifested by an increased RV and hyperinflation manifested by an increased FRC and TLC.
COPD = chronic obstructive pulmonary disease; FRC = functional residual capacity; OVD = obstructive ventilatory dysfunction; RV = residual volume; TLC = total lung
capacity.

TABLE 222
GOLD Criteria for Chronic Obstructive Pulmonary Disease Severity
STAGE DESCRIPTION FINDINGS (BASED ON POSTBRONCHODILATOR FEV1)
0 At risk Risk factors and chronic symptoms but normal spirometry
I Mild FEV1/FVC 70%
FEV1 at least 80% of predicted value
May have symptoms
II Moderate FEV1/FVC 70%
FEV1 50% to < 80% of predicted value
May have chronic symptoms
III Severe FEV1/FVC 70%
FEV1 30% to < 50% of predicted value
May have chronic symptoms
IV Very severe FEV1/FVC 70%
FEV1 < 30% of predicted value
or
FEV1 < 50% of predicted value + chronic respiratory failure
Respiratory failure: PaO2 < 60 mm Hg with or without PaCO2 > 50 mm Hg
while breathing room air at sea level
FEV1 = postbronchodilator forced expiratory volume in 1 second; FVC = forced vital capacity; PaCO2 = arterial partial pressure of carbon dioxide; PaO2 = arterial
partial pressure of oxygen.
From Rabe KF, Hurd S, Anzueto A, et al: Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of
chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2007;176:532555.

hyperinflation and even hypercapnic respiratory failure.

Patients with COPD and predominantly chronic bronchitis
typically have recurrent exacerbations and tend to have
lower arterial partial pressure of oxygen (PaO2) values earlier
in the disease course. Some may develop hypercapnia and
cor pulmonale (blue bloaters). Other OVD patients have
predominantly emphysema with severe hyperinflation (due
to loss of lung elastic recoil) and relative preservation of PaO2
levels until late in the disease course. They present with
dyspnea and, because of the relatively spared PaO2, are called
pink puffers.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
COPD is the fourth leading cause of death in the United
States.4 The major cause of COPD is cigarette smoking.
Patients with COPD may die from respiratory failure or lung
cancer. Although they typically present to physicians with
complaints of bronchitis or dyspnea, they also frequently
complain of poor-quality sleep. The Global Initiative for
Chronic Obstructive Lung Disease (GOLD) has defined
severity criteria (Table 222).4 In general, an FEV1 less
than 30% to 40% of predicted or 1.0 L for a normal-sized
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 412 Chapter 22 Sleep and Obstructive Lung Disease

100 Lights out Time

90 100
90
80 A
80
Arterial oxygen saturation (%)

70 70
60
60

SpO2
50
50 40
15 minutes
30
40
20
30 10
0
20
FIGURE 224 A portion of overnight oximetry in a patient with both snoring and
10 moderate COPD. The baseline is reduced during sleep but the saw-tooth pattern is
suggestive of obstructive sleep apnea. A = period of REM sleep. From Berry RB: Sleep
0 Medicine Pearls 2nd ed. Philadelphia: Hanley & Belfus, 2003, p. 227.
11 12 1 2 3 4 5 6 7
PM AM
Time of night

FIGURE 223 Nocturnal oximetry in a patient with severe chronic obstructive BOX 221
pulmonary disease (COPD). The awake arterial oxygen saturation (SaO2) is mildly Major Mechanisms of Nocturnal Oxygen
reduced at 92% but falls to the low 80s with sleep. Further severe falls in the SaO2 occur Desaturation in Chronic Obstructive
during rapid eye movement (REM) sleep (dark bars). Note that the worst period of Pulmonary Disease
desaturation was noted in the early morning hours. From Berry RB: Sleep Medicine
Pearls, 2nd ed. Philadelphia: Hanley & Belfus, 2003, p. 216. Hypoventilationbelieved by most to be the most
important factor
Decreased chemosensitivity (REM < NREM < wake)
Reliance on accessory respiratory muscles and loss of
individual indicates very severe disease. Daytime hypercap- this assistance during REM atonia
nia is usually associated with an FEV1 of 30% to 40% of Increased upper airway resistance
predicted or less. Patients with the overlap syndrome (COPD Lower alveolar ventilation per minute ventilation (high
+ obstructive sleep apnea [OSA]) can develop hypercapnia dead spacetotidal volume ratiodue to high dead
with higher FEV1 values. space and low tidal volume)
Ventilation-perfusion mismatching (drop in PaO2 exceeds
the increase in PaCO2)
Sleep in COPD
High closing volume and decreases in FRCespecially
Sleep in patients with COPD is often impaired in both dura- during REM-associated hypopnea
tion and quality.57 Many patients also have significant Coexisting sleep apnea (1215%)especially blue
hypercapnia and hypoxemia at night. Ten percent to 15% of bloaters
patients may also have concomitant OSA that worsens noc- Low awake SaO2starting position on the steep portion
turnal gas exchange (overlap syndrome). The typical pattern of the oxygen-hemoglobin saturation curve (larger fall in
of nocturnal oxygen desaturation (NOD) in a patient with SaO2 for a given fall in PaO2)
COPD is shown in Figure 223. The baseline sleeping arte- FRC = functional residual capacity; NREM = nonrapid eye movement;
PaCO2 = arterial partial pressure of carbon dioxide; PaO2 = arterial partial
rial oxygen saturation (SaO2) falls 2% to 4% from the awake pressure of oxygen; REM = rapid eye movement; SaO2 = arterial oxygen
baseline with minor fluctuations until much larger drops are saturation.
noted during rapid eye movement (REM; stage R) sleep. In
contrast, a typical oximetry of a patient with the overlap
syndrome is shown in Figure 224. There is a low baseline
sleeping SaO2 and a saw-tooth pattern consistent with mechanisms of nocturnal arterial oxygen desaturation are
repeated discrete events. Whereas central sleep apnea could listed in Box 221. The relative importance of hypoventila-
cause a saw-tooth pattern, this is most likely to represent   mismatch is still
tion and ventilation-perfusion ( V/Q)
OSA. debated.

Etiology of Abnormal Nocturnal Gas Exchange Normal Individuals

Patients with COPD often experience exaggerations of During nonrapid eye movement (NREM) sleep, CO2 pro-
normal sleep-related changes in ventilation. The most duction falls but alveolar ventilation falls proportionately
severe desaturation occurs during REM sleep. The major more and arterial pressure of carbon dioxide (PaCO2)
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 Chapter 22 Sleep and Obstructive Lung Disease 413

increases slightly (Fig. 225). Recall that PaCO2 = constant
(CO2 production)/(alveolar ventilation); see Chapter 10.
The fall in ventilation is due to a loss of the wakefulness
stimulus to breathe, decreased ventilatory responses (che-
mosensitivity) to hypoxia and hypercapnia, and increased
upper airway resistance.5,7 The increase in PaCO2 results in
a mild decrease in the PaO2. However, because the awake
PaO2 value is on the flat portion of the oxygen-hemoglobin
saturation curve (Fig. 226), minimal drops in the SaO2 are
noted (e.g., from 97% to 95%). The FRC may decrease slightly
from wake to NREM sleep (Fig. 227).8,9
During REM sleep in normal individuals, ventilation is
irregular and periods of reduced tidal volume occur, often
during bursts of REMs. Skeletal muscle hypotonia reduces
the contribution from the accessory respiratory muscles and
respiration depends on the diaphragm.8,9 Two studies did not
find a lower FRC during REM compared with NREM sleep
in normal individuals (see Fig. 227).8,10 During REM sleep,
there is typically a decrease in chest wall movement,9 likely
due to chest wall hypotonia. These REM-associated physio-
logic changes result in a slight increase in PaCO2 and
decreases in PaO2 during REM compared with NREM sleep.
The slight fall in PaO2 results in minimal changes in the SaO2
due to the position of the oxygen-hemoglobin saturation
curve (see Fig. 226).
Sleep-Related Changes in Respiration in COPD
Koo and colleagues11 studied 15 patients with severe COPD
(FEV1 of 0.96 L) with a mean daytime PaO2 greater than
10 mmHg decrease in PO2
causes a greater desaturation
starting on the steeper part of
the curve
100

% Oxygen saturation (SaO2)

Loss of 80
Metabolic rate
wakefulness
stimulus 10-15%
60

Upper 40
Ventilation Chemosensitivity
airway
resistance 0.5-1.5 LPM 20-50%
20

PaCO2 2-8 mmHg 0

PaO2 3-10 mmHg 20 40 60 80 100
SaO2 1-2% PaO2 (mmHg)
Oxygen-hemoglobin Dissociation Curve
FIGURE 225 Normal changes in gas exchange during sleep. PaCO2 = arterial partial
pressure of carbon dioxide; PaO2 = arterial partial pressure of oxygen; SaO2 = arterial FIGURE 226 The same drop in the arterial partial pressure of oxygen (PaO2) is
oxygen saturation. Adapted from Mohsenin V: Sleep in chronic obstructive pulmonary associated with a greater drop in the arterial oxygen saturation (SaO2) when the initial
disease. Semin Respir Crit Care Med 2005;26:109115. partial pressure of oxygen (PO2) is 60 rather than 80 mm Hg.

NORMAL ASTHMA ASTHMA VS NORMAL

Wake  stage N2  Wake  stage N2  FRC higher wake,
stage N3  stage R stage N3  stage R stage N2, stage N3
4.0 4.0 4.0

*P  .05
* *P  .05 *P  .05
3.5 3.5 3.5 *
*
*
FRC (liters)

FRC (liters)

FRC (liters)

3.0 * 3.0 3.0

Asthma

2.5 2.5 * 2.5

Wake  stage N2  Normal

stage N3  stage R
2.0 2.0 2.0
W 2 34 REM W 2 34 REM W 2 34 REM
Sleep stages Sleep stages Sleep stages

FIGURE 227 (Left) In normal subjects the FRC is lower during sleep but the FRC does not differ between stages 2, 34, and REM (N2, N3, and R). (Middle) In asthma the FRC
decreases from wake to stage N2N3 and then further decreases during REM sleep. (Right) FRC during wake and stages N2 and N3 is higher in asthmatics compared to normal
individuals. In this study the FRC during REM sleep was similar in asthmatics and normal individuals. FRC = functional residual capacity; REM = rapid eye movement. Adapted from
DaneshGroup.com
Ballard RD, Irvin CG, Martin RJ, et al: Influence of sleep on lung volume in asthmatic patients and normal subjects. J Appl Physiol 1990;68:20342041.
414 Chapter 22 Sleep and Obstructive Lung Disease

60 mm Hg and found a mean decrease in PaO2 of 13.5 mm Hg COPD exhibit REM-related hypoventilation and NOD,
and a mean increase in PaCO2 of 8.3 mm Hg during REM despite having a daytime PaO2 above 60 mm Hg.12
sleep (Fig. 228). Although patients with daytime hypercap-
nia or a low awake PaO2 or SaO2 are more likely to have NonRapid Eye Movement During supine wakefulness, patients
worse gas exchange during sleep, up to 25% of patients with with COPD often start with low-normal or slightly decreased
SaO2 values. Therefore, even the normal fall in PaO2 with
80 sleep will cause a greater decrease in the SaO2. Koo and col-
leagues11 documented a fall in PaO2 of approximately
8 mm Hg from wake to NREM sleep and an increase in
 Mean 1 SD
PaCO2 of about 5 mm Hg. In patients with COPD, the onset
of NREM sleep is associated with mild falls in the SaO2 (4
Partial pressure arterial O2 and CO2 (mmHg)

70 8%) and PaCO2 increases. If obstructive apneas or hypop-

neas are present, the degree of desaturation is worsened. Due
to hyperinflation, the diaphragm is at a mechanical disad-
vantage and there is more dependence on the accessory
muscles of respiration. In a study by Becker and coworkers13
60 of a group of hypercapnic patients with COPD, the minute
PaO2
ventilation fell by 16% from wake to NREM.

Rapid Eye Movement During REM sleep, there are more pro-
PaCO2 found periods of arterial oxygen desaturation compared with
50 NREM sleep in patients with COPD. These episodes of desat-
uration are characterized by long periods of irregular breath-
ing and reduced tidal volume (Figs. 229 and 2210). In
contrast to obstructive hypopnea in OSA patients, the onset
and termination of these nonapneic periods of REM desatu-
40
ration are less well defined. As noted previously, it is believed
Awake 2 3 REM that REM-associated hypotonia reduces the contribution for
Stages of sleep the intercostal muscles so that ventilation depends on the
diaphragm. Hyperinflation in patients with COPD reduces
FIGURE 228 Changes in arterial partial pressure of carbon dioxide (PaCO2) and
the effectiveness of the diaphragm. During the periods of
arterial partial pressure of oxygen (PaO2) during sleep in a group of patients with severe
COPD. Here stages 2, 3, and REM represent stages N2, N3, and R. REM = rapid eye
REM-associated diaphragmatic inhibition (often during
movement; SD = standard deviation. From Koo KW, Sax DS, Snider GL: Arterial blood bursts of eye movements),1315 the tidal volume and minute
gases and pH during sleep in chronic obstructive pulmonary disease. Am J Med ventilation often decrease dramatically (see Figs. 229 and
1975;58:663670.

Wake
Sleep stage

1
2
3
REM
REM
100
O2 saturation %

90
80
70
60
50
Tidal volume

500 cc

1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time in minutes

FIGURE 229 An episode of hypopneic breathing during rapid eye movement (REM) sleep in a patient with COPD. The episode lasted over 10 minutes. From Fletcher EC, Gray BA,
Levin DC: Nonapneic mechanisms of arterial oxygen desaturation during rapid-eye-movement sleep. J Appl Physiol 1983;54:632639.
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 Chapter 22 Sleep and Obstructive Lung Disease 415

1.4 20 FIGURE 2210 Fall in tidal volume during a period of rapid eye
movement (REM)associated hypoventilation. Note that there is no
Respiratory rate
1.2 overall significant change in the respiratory rate. NREM = nonrapid eye
movement. From Becker HF, Piper AJ, Flynn WE, et al: Breathing during
15
1.0 sleep in patients with nocturnal desaturation. Am J Respir Crit Care Med

Breaths per minute

1999;159:112118.
0.8
10
0.6 3 min

Tidal volume
0.4
5

0.2
NREM REM NREM
0 0
0 20 40 60 80
Breaths

EEG sleep stage 3: PaO2 44 mmHg

the usual blood gas analysis of the relationship between PaO2
80
PaCO2 50 mmHg and PaCO2 depends on an assumption of steady state. This
condition does not exist during the transient periods of
Ear SaO2 (%)

hypopneic breathing. Because oxygen stores in the body are

Chest 0 1
min
movement
50
0 1
min
REM sleep: PaO2 37 mmHg
4:00am 5:00am
PaCO2 54 mmHg
Time
FIGURE 2211 An episode of rapid eye movement (REM)associated nonapneic
desaturation in a patient with COPD. The decrease in arterial partial pressure of oxygen
(PaO2) was greater than the increase in the arterial partial pressure of carbon dioxide
(PaCO2). Stage 3 and REM denote stages N3 and R. EEG = electroencephalogram;
SaO2 = arterial oxygen saturation. From Catterall JR, Calverley PMA, MacNee W, et al:
Mechanism of transient nocturnal hypoxemia in hypoxic chronic bronchitis and emphysema.
J Appl Physiol 1985;59:16981703.
2210). The drop in alveolar ventilation is even larger than
the change in minute ventilation due to an increase in the
dead spacetotidal volume ratio (see Chapter 10). In one
study of a group of hypercapnic patients with COPD, the
minute ventilation fell by 32% from wake to REM sleep
(compared with 16% from wake to NREM).13 Studies have
documented increases in PaCO2 during these episodes.11,15,16
Figure 2210 illustrates a nonapneic period of REM-
associated fall in tidal volume.
  Mismatch Whereas hypoventilation definitely occurs
V/Q
during periods of nonapneic desaturation (also called hypop-
neic breathing), Catterall and associates16,17 directly mea-
sured arterial blood gases and found the PaO2 dropped more
than the PaCO2 increased (Fig. 2211). Therefore, increased
  mismatch is believed to play a role in REM-associated
V/Q
desaturation (in addition to hypoventilation).15,16 However,
as Catterall and associates16,17 and others have pointed out,
much smaller than carbon dioxide stores, a change in venti-
lation may affect PaO2 more than PaCO2.
Many patients with COPD have an increase in FRC in the
upright position (hyperinflation). In the supine position, the
FRC may be slightly lower during wakefulness. Ballard and
coworkers10 found similar FRC values during wake, NREM,
and REM sleep in patients with emphysema. However, in
asthmatics, another study found that the FRC does decrease
from wake to NREM and from NREM to REM (see Fig.
227).10 COPD patients with a significant component of
airways disease could experience a drop in FRC during REM
sleep. In a given patient with COPD, the FRC may also be
affected by the degree of obesity. Furthermore, assigning a
single FRC value to stage R sleep is problematic because
breathing during REM sleep is very inhomogeneous. Hudgel
and coworkers14 found no decrease in FRC during transition
from stage N2 to stage R sleep in a group of five patients with
COPD. However, during episodes of hypopneic breathing
in REM sleep, there was a fall in FRC. The same study
found that those COPD patients who desaturated during
REM sleep had longer periods of hypopneic breathing (Fig.
2212). Thus, it seems likely that the FRC during hypopneic
breathing in COPD is lower than during NREM sleep.
Whether the absolute value is below normal may vary
between patients.
A fall in the FRC during hypopneic breathing in COPD
patients may have greater consequences than in normal indi-
viduals. In COPD, the closing volume (CV), the volume at
which small airway closure is significant, is closer to the FRC
than in normal individuals. During the hypopneic breathing
of REM sleep, the FRC falls below the CV (Fig. 2213). This
means that during tidal breathing, more alveoli are either not
ventilated or underventilated. This results in worsening of
  mismatch (already abnormal awake) and worsening
V/Q
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416 Chapter 22 Sleep and Obstructive Lung Disease

FIGURE 2212 Hypopnea and hyperpnea in REM sleep

in a COPD patient. Raw intercostal and diaphragmatic
electromyogram (EMG), esophageal pressure, and arterial Intercostal EMG
oxygen saturation (SaO2) are shown. This is the end of an
episode of REM hypopneic breathing. Note the increase in end-
expiratory volume (*) at the end of the episode. The solid bar
shows that the end-expiratory volume after the hypopnea ends Diaphragm EMG
is higher than during the hypopneic breathing. Also note the
decreased intercostal EMG and greater reduction in chest wall 100
80
movement. From Hudgel DW, Martin RJ, Capehart M, et al: 60
Contribution of hypoventilation to sleep oxygen desaturation Oxygen saturation 40
20
in chronic obstructive pulmonary disease. J Appl Physiol 1983; 0
55:669677.
Chest volume 0.5 L

Abdominal volume 0.5 L

*
Total volume 0.5 L

10 cm
Esophageal pressure
H2O

Normal COPD hypopneic breathing during REM sleep are still debated. The
analysis is complicated by the nonsteady-state condition of
transient hypopneic breathing.
FRC
FRC Time of Night and Circadian Variation in Lung Function
CV REM episodes in the early morning have greatest REM
CV
density and the greatest variation in ventilation even in
normal individuals.19 These REM periods also are typically
longer. In the early morning hours, there is greater lower
Awake REM Awake REM
airway resistance due to circadian changes in bronchomotor
supine supine supine (hypopneic tone that are exaggerated in many patients with COPD.5,6
breathing Ballard and colleagues18 found an increase in upper airway
supine) resistance but not lower airway resistance during the night
FIGURE 2213 In patients with chronic obstructive pulmonary disease (COPD), the in a group of patients with emphysema. Conversely, lower
closing volume (CV) is nearer the functional residual capacity (FRC) than in normal airway resistance does increase in asthmatics20 and likely in
individuals. The fall in FRC associated with hypopneic breathing during rapid eye some COPD patients with a significant component of airway
movement (REM) sleep results in tidal breathing below the CV. This worsens ventilation- disease. These factors help explain why the most severe and
perfusion mismatch. Note that, in this figure, the FRC for COPD during hypopneic longest REM-associated desaturation typically occurs in
breathing in REM sleep is shown as approximately equal to that of a normal individual the early morning hours.
during REM sleep. The actual FRC in COPD patients may depend on other factors such as
obesity and vary between individuals.
COPD Types and Respiration during Sleep
Several studies have tried to find factors predicting more
severe desaturation during sleep in COPD. As might be
expected, a lower awake PaO2 and higher PaCO2 predict
hypoxemia. Hudgel and coworkers14 concluded that hypoven- more dramatic changes in gas exchange during sleep. One
  mismatch, causes REM-
tilation, and to a lesser extent V/Q study compared blue bloaters and pink puffers and found the
associated desaturation. Fletcher and associates15 found an former were more likely to desaturate during sleep (Table
increase in venous admixture during REM hypopnea epi- 223).21 Analysis of the Sleep Heart Health data suggested
sodes and concluded that V/Q   mismatch was a significant that the odds of having desaturation more than 5% of total
cause of hypoxemia. The relative roles of hypoventilation and sleep time was minimally increased until the FEV1/FVC ratio
  mismatch in inducing nocturnal desaturation during was less than 60% (Table 224).22 A plot of awake SaO2 versus
V/Q
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 Chapter 22 Sleep and Obstructive Lung Disease 417

TABLE 223 TABLE 224

Arterial Oxygen Saturation during Wake and Adjusted Odds of Desaturation > 5% of Total
SleepVariation with Chronic Obstructive Sleep Time*
Pulmonary Disease Type FEV1/FVC ADJUSTED ODDS RATIO
PINK BLUE
>80 1.0
PUFFER (%) BLOATER (%)
75.979.9 0.92
SaO2 awake and sitting 93 88.4
70.074.9 1.01
SaO2 awake and supine 92.3 80.5
65.069.9 1.32
SaO2 sleep 92.3 77.3
6064.9 1.92
Maximal fall in SaO2 4.7 29.5
<60 3.36
Episodes of arterial 3.5 22.7
oxygen desaturation *Excludes subjects with AHI > 15/hr.
AHI = apnea-hypopnea index; FEV1 = forced expiratory volume in 1 second;
SaO2 < 80% (min) 0.08 120.0 FVC = forced vital capacity.
From Sanders MH, Newman AB, Haggerty CL, et al: Sleep and sleep-
From DeMarco FJ Jr, Wynne JW, Block AJ, et al: Oxygen desaturation during disordered breathing in adults with predominantly mild obstructive airway
sleep as a determinant of the blue and bloated syndrome. Chest disease. Am J Respir Crit Care Med 2003;167:714.
1981;79:621625.

100 100 FIGURE 2214 The relationship between mean

arterial oxygen saturation (SaO2) during wakefulness
and the mean overnight SaO2 during sleep (left) or
lowest SaO2 asleep (right). The closed and open circles
80 80 represent patients from different centers. From
Connaughton JJ, Catterall JR, Elton RA, et al: Do sleep
Mean overnight SaO2 (%)

studies contribute to the management of patients with

Lowest SaO2 asleep (%)

severe chronic obstructive pulmonary disease? Am Rev

60 60 Respir Dis 1988;138:341344.

40 40

20 20

0 0
60 70 80 90 100 60 70 80 90 100
Mean SaO2 awake (%) Mean SaO2 awake (%)

minimum sleeping value is shown in Figure 2214. Patients oxygen found no difference in quality of life, subjective sleep-
with lower awake SaO2 or PaO2 values tend to have lower iness, or subjective sleep quality in COPD patients who had
values at night.23 However, there is considerable variability NOD compared with those who did not.24 It is likely that
and oximetry or polysomnography (PSG) is needed to reli- other factors such as cough, nocturnal dyspnea, and medica-
ably exclude NOD. tion side effects have greater effect than transient hypoxemia
on sleep quality. In many patients, the NOD is less than 15
Sleep Quality in COPD minutes and confined to the last few REM periods of the
Sleep quality is impaired with reductions in total sleep time, night.
stage N3 sleep, and REM sleep. In contrast, the wake after
sleep onset (WASO) and stage N1 sleep are increased as is Treatment of Sleep-Related Hypoxemia in COPD
the total arousal index. Patients often complain of insomnia Studies have shown that long-term oxygen therapy (LTOT)
but can also complain of daytime sleepiness if OSA is also will improve survival in patients with COPD with daytime
present. A study of NOD in COPD patients not on 24-hour hypoxemia.2527 The standard indication for 24-hour
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418 Chapter 22 Sleep and Obstructive Lung Disease
BOX 222
Indications for Supplemental Oxygen
Local Carrier Determination (LCD) 11446 (Cigna) for CMS
240.2 National Carrier Determination
GROUP I (INITIAL COVERAGE LIMITED TO 12 MO)
1. PO2 55 mm Hg or SaO2 88% at rest awake (breathing
room air, stable medical condition).
2. PO2 55 mm Hg or SaO2 88% for at least 5 min while
asleep. Oxygen is provided during sleep only.
3. Decrease in PO2 > 10 mm Hg or a decrease in SaO2 5%
for at least 5 min during sleep associated with
symptoms.*
4. PO2 < 55 mm Hg or SaO2 88% during exercise in a
patient with a PaO2 at 56% or SaO2 89% at rest.
Oxygen provided during exercise.
GROUP II (INITIAL COVERAGE LIMITED TO 3 MO)
The presence of (a) an arterial PO2 of 5659 mm Hg
or an arterial oxygen saturation of 89% at rest (awake),
during sleep for at least 5 min, or during exercise (as
described in Group 1 criteria) and (b) any one of the
following:
1. Dependent edema suggesting CHF.
2. Pulmonary HTN or cor pulmonale determined by
measurement of pulmonary artery pressure, gated blood
pool scan, echocardiogram, or P pulmonale on ECG
(P wave 3 mm in standard leads II, III, or aVF) or
3. Erythrocythemia with Hct > 56%.
4. PaO2 55 mm Hg or SaO2 88% during exercise,
O2 supplied only for exercise.
See also CMS 240.2 NCD for Home Oxygen
L11446 can be found at https://www.virtuox.net/
dyndocs/Documents/LCDforOxygen.pdf
*Symptoms: impairment of consciousness, nocturnal restlessness, insomnia
or signs of cor pulmonale, P pulmonale on ECG, documented pulmonary
HTN, erthyrocytosis.
CHF = congestive heart failure; CMS = Centers for Medicare and Medicaid
Services; ECG = electrocardiogram; Hct = hematocrit; HTN = hypertension;
PaO2 = arterial partial pressure of oxygen; PO2 = partial pressure of oxygen;
SaO2 = arterial oxygen saturation.
supplemental oxygen is a daytime PaO2 55 mm Hg at rest
when the patient is in stable condition. PaO2 values from 56
to 59 mm Hg are also an indication of a need for oxygen
therapy if signs of dysfunction (right heart failure) are
present. Typical requirements for Medicare reimbursement
for supplemental oxygen are listed in Box 222. The criteria
vary between regions (Local Carrier Determinations).
Patients qualifying for 24-hour supplemental oxygen will
obviously be using nocturnal oxygen. However, one study
found that at least 50% of patients on LTOT needed increased
oxygen flow during sleep.28 The utility of treating isolated
NOD (daytime PaO2 > 60 mm Hg) is unproven. However,
most clinicians would treat patients who have a nocturnal
SaO2 less than 88% for a substantial period of time. Most
insurance providers require at least 5 minutes less than or
equal to 88% (see Box 222).
TABLE 225
Studies of Effects of Supplemental Oxygen on
Sleep Quality in Chronic Obstructive Pulmonary
Disease
CALVERLY29 FLEETHAM30
(N = 6) (N = 15)
Total sleep time Increased No change
Stage N3 Increased No change
REM sleep Increased No change
Arousals Decreased No change
REM = rapid eye movement.
One study found an improvement in sleep quality with
supplemental oxygen,29 and another did not.30 Both were
relatively small studies and this question remains to be
answered (Table 225). A randomized trial of supplemen-
tal oxygen in patients with isolated NOD (daytime PaO2 >
60 mm Hg) did not find a survival benefit (although there
were only a small number of deaths) but nocturnal oxygen
did improve the pulmonary artery pressure.31 Chaouat and
coworkers32 also performed a randomized trial of noctur-
nal oxygen in a similar patient group. They found no
benefit of oxygen treatment with respect to mortality, the
increase in pulmonary artery pressure, or the subsequent
need for daytime oxygen. Connaughton and colleagues23
found that those patients with a worse NOD than expected
based on daytime gas exchange did not have a worse prog-
nosis and argued against the use of routine sleep studies or
nocturnal oximetry in COPD patients. On the other hand
nocturnal oximetry is indicated if the patient complains
of nocturnal symptoms or has evidence of cor pulmonale.
In acute respiratory failure, administration of high-flow
oxygen can significantly worsen hypercapnia but low-flow
supplemental oxygen produces only mild to moderate
increases in nocturnal PaCO2 unless patients have sleep
apnea33 (Fig. 2215). Another study found that increasing
the nocturnal oxygen flow rate by even 1 L/min resulted in
a lower pH and higher PaCO2 in the morning.34 It seems
prudent to use the lowest oxygen flow required to maintain
adequate nocturnal oxygenation, especially in hypercapnic
patients.
Bronchodilators Treatment with bronchodilators, especially
long-acting inhaled bronchodilators, does improve noctur-
nal oxygenation in COPD patients. Most studies of the
effects of bronchodilators on sleep have not shown improve-
ment in sleep quality. Conversely, quality was usually not
worsened. One study compared the combination of
sustained-action theophylline and a short-acting inhaled
beta agonist bronchodilator at bedtime versus the inhaled
bronchodilator + placebo.35 The addition of theophylline did
not worsen sleep quality but improved the morning FEV1
DaneshGroup.com

100
Room air
80
SaO2 (%)
TcPCO2 (mm Hg)
60
40
Oxygen
100
SaO2 (%)
TcPCO2
TcPCO2 (mm Hg)
80
FIGURE 2215 Top, The arterial oxygen saturation (SaO2) and transcutaneous partial pressure of carbon dioxide (TcPCO2) during the
night with an impressive drop in the SaO2 during rapid eye movement (REM) sleep associated with a mild increase in the TcPCO2. The
TcPCO2 is approximately 70 mm Hg during NREM sleep. Bottom, The same patient on supplemental oxygen with a TcPCO2 now
approximately 80 mm Hg. There is improved SaO2, although the TcPCO2 increases during REM sleep. From Goldstein RS, Ramcharan V,
Bowes G, et al: Effect of supplemental nocturnal oxygen on gas exchange in patients with severe obstructive lung disease. N Engl J Med
1984;310:425429.
and SaO2 during NREM sleep.35 Martin and associates36
found that inhaled ipratropium bromide (a short-acting
anticholinergic) given by nebulizer improved subjective
sleep quality, NOD, and the amount of REM sleep. This study
used 4 nights of sleep monitoring, allowing patients to
acclimate to the monitoring equipment. McNicholas and
coworkers37 found that tiotropium (a long-acting inhaled
anticholinergic) given either in the morning or in the evening
improved the SaO2 during REM sleep compared with placebo
but did not improve sleep quality. Ryan and colleagues38
found that salmeterol, a long-acting inhaled beta agonist,
improved nocturnal oxygenation without impairing sleep
quality. Donahue and associates39 compared fluticasone
propionate/salmeterol with ipratropium bromide/albuterol
during an 8-week period. The former treatment combination
was more effective at reducing nocturnal and sleep symp-
toms. The use of inhaled corticosteroids in patients with
COPD remains somewhat controversial and the controversy
was reviewed by Sin and Man.40 The use of inhaled cortico-
steroids does not improve mortality but, in some studies,
improved the quality of life, reduced exacerbations, and
improved lung function when added to a long-acting bron-
chodilator. Based on the previously mentioned studies, most
clinicians would use a long-acting beta agonist or anticho-
linergic in patients with significant COPD who complain of
nocturnal dyspnea, cough, or poor sleep quality. Inhaled
corticosteroids are also a reasonable addition especially if the
patient has repeated COPD exacerbations, a significant com-
ponent of bronchospasm, or do not respond to other
treatments.
Chapter 22 Sleep and Obstructive Lung Disease 419
SaO2
TcPCO2
REM
10 min
SaO2
REM
Hypnotics in COPD Patients Hypnotics have been used with
some caution in patients with COPD. In general, in nonhy-
percapnic patients, clinically significant worsening of gas
exchange does not occur with benzodiazepine receptor ago-
nists.41 Girault and coworkers42 studied 10 patients with
severe COPD before and after 10 days of zolpidem 10 mg
and could find no worsening in performance or gas exchange.
Of interest, the only objective improvement in sleep was an
increase in stage N2. Subjective sleep quality was also
improved (not placebo-controlled). Another study found no
detrimental effects from temazepam 10 mg.43 Steens and col-
leagues44 studied the effects of zolpidem and triazolam in
mild to moderate COPD. Total sleep time was increased as
well as sleep efficiency without an adverse effect on gas
exchange. This was a randomized, double-blind, placebo-
controlled study. A double-blind, placebo-controlled cross-
over study of patients with moderate to severe COPD
evaluated the effects of 8 mg of ramelteon, a melatonin
agonist with no respiratory depressant properties. This study
found no worsening of nocturnal gas exchange.45 However,
there was an improvement in total sleep time, sleep effi-
ciency, and the latency to persistent sleep on ramelteon com-
pared to placebo. This medication has a short duration of
action and is generally used for sleep-onset insomnia.
However, the duration of action may vary between individu-
als. In summary, the benzodiazepine receptor agonists are
probably safe in nonhypercapnic nonhypoxemic patients.
However, caution is still required. Ramelteon is a safe hyp-
notic that may be effective in some patients with COPD.
Many clinicians use sedating antidepressants as hypnotics
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420 Chapter 22 Sleep and Obstructive Lung Disease
(e.g., trazodone), believing that this is safer. However, the
utility of the use of sedating antidepressants to improve sleep
quality in COPD patients has never been documented.
Nocturnal Noninvasive Positive-Pressure Ventilation For patients
with COPD who present with hypercapnic respiratory
failure, noninvasive positive-pressure ventilation (NPPV)
has proved to be an effective treatment, often avoiding the
need for intubation and mechanical ventilation. The results
for long-term use are much less clear. Those COPD patients
most likely to benefit are individuals with substantial daytime
CO2 retention and NOD who are highly motivated. A con-
sensus conference recommended the following indications
for NPPV in patients with COPD46:
1. Symptoms criteria (e.g., fatigue, dyspnea, or morning
headache),
2. Physiologic criteria daytime PaCO2 > 55 or 5054 mm Hg
with NOD, or
3. PaCO2 5054 mm Hg with recurrent hospitalization
related to episodes of hypercapnic respiratory failure.
Patients with severe swallowing dysfunction or those who
cannot protect their airway are not candidates for NPPV.
Overlap Syndrome
The overlap syndrome (OLS) consists of patients with both
OSA and COPD (Box 223). One study found that OSA is
no more frequent in COPD patients than in the general
population.22 That is, the prevalence of OSA in COPD
patients is the same as in the general population. However,
because both are common, the combination is also fairly
common. The two groups of OSA patients with daytime
hypercapnia include patients with the obesity hypoventila-
tion syndrome and some patients with OLS.4749 Patients
with OLS tend to have severe NOD even if they do not have
daytime hypercapnia. Patients with COPD usually become
hypercapnic when the FEV1 is around 1.0 liters (or 40% of
predicted). OLS patients can be hypercapnic with milder
reductions in the FEV1 (Table 22-6, Study #2). However, OLS
patients can also maintain a normal daytime PCO2 even
when their FEV1 is quite reduced (Table 22-6, Study #1). In
clinical practice, one often treats patients with a combination
of COPD, OSA, and severe obesity who have significant
hypoventilation. It is difficult to know how to label them
because they likely have components of both OHS and OLS.
Treatment of OLS
Treatment of patients with OLS with supplemental oxygen
alone can result in significant increases in nocturnal PaCO2.
In Figure 2216, on room air, there is a saw-tooth pattern in
the SaO2 tracing. As mentioned previously, this is a clue that
OSA as well as COPD is present. On the bottom, the patient
is on supplemental oxygen and the transcutaneous partial
pressure of carbon dioxide (TcPCO2) has climbed from
approximately 60 mm Hg (top tracing) to just below
BOX 223
Overlap Syndrome
Combination of OSA and COPD.
Prevalence of OSA in COPD is the same as the general
population.
Predisposes OSA patients to more severe arterial oxygen
desaturation.
Hypercapnia may occur in OLS at FEV1 values greater than
typically associated with hypercapnia in patients with
COPD without OSA.
Optimal treatment of OLS
PAP (CPAP or BPAP), BPAP may be better tolerated.
Supplemental oxygen if needed (low awake or
baseline sleeping SaO2).
Bronchodilator treatment and smoking cessation.
Nocturnal supplemental oxygen alone is not adequate
treatment, may be associated with significant
hypercapnia during sleep and worse outcomes.
OLS patients who adhere to CPAP (in addition to oxygen
if needed) have a better outcome.*
OLS patients have an increased risk of death and
hospitalization due to severe COPD exacerbations.
Treatment with CPAP may improve survival of OLS
patients and decrease hospitalizations.
*From Machado MCL, Vollmer WM, Togeiro SM, et al: CPAP and survival in
moderate to severe obstructive sleep apnea syndrome and hypoxemic COPD.
Eur Respir J 2010;35:132137.
From Marin JM, Soriano JB, Carrizo SJ, et al: Outcomes in patients with
chronic obstructive pulmonary disease and obstructive sleep apnea. Am J
Respir Crit Care Med 2010;182:325331.
BPAP = bilevel positive airway pressure; COPD = chronic obstructive
pulmonary disease; CPAP = continuous positive airway pressure; FEV1 =
forced expiratory volume in 1 second; OLS = overlap syndrome; OSA =
obstructive sleep apnea; PAP = positive airway pressure; SaO2 = arterial
oxygen saturation.
90 mm Hg. Therefore, use of supplemental oxygen in patients
with OLS and significant daytime hypercapnia may worsen
nocturnal hypercapnia. Fletcher and associates50 followed
patients with chronic lung disease and OSA including a
group treated with oxygen but no effective treatment for
sleep apnea. They found that patients who did not have ade-
quate treatment for OSA had no improvement in their pul-
monary hemodynamics whereas those who had effective
treatment improved. A recent observational study of patients
with OSA and hypoxemic COPD receiving LTOT found that
those who accepted continuous positive airway pressure
(CPAP; in addition to oxygen) and adhered to treatment had
a better survival than those who did not.51 Another study by
Marin and coworkers52 of patients with OLS found an
increased risk of death and hospitalization due to COPD
exacerbations. CPAP treatment was associated with improved
survival and decreased hospitalizations. The treatment of
patients with OLS includes treatment of their COPD and
CPAP or bilevel positive airway pressure (BPAP) with sup-
plemental oxygen if needed. If significant CO2 retention is
present, most clinicians would use BPAP. Some patients with
COPD have difficulty exhaling on CPAP and may be more
adherent to treatment with BPAP.
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 Chapter 22 Sleep and Obstructive Lung Disease 421

FIGURE 2216 A patient with obstructive sleep

SaO2 apnea (OSA) and COPD. Top, A saw-tooth pattern in
Room air
70
the arterial oxygen saturation (SaO2) is noted while
the patient breathes room air. The transcutaneous
60 partial pressure of carbon dioxide (TcPCO2) is
SaO2 (%)
TcPCO2 approximately 60 mm Hg and the SaO2 is severely
50
TcPCO2 (mm Hg) reduced. Bottom, The patient is breathing
40 supplemental oxygen. The SaO2 is improved but the
TcPCO2 has increased dramatically to just below
30
90 mm Hg. From Goldstein RS, Ramcharan V, Bowes
100 Oxygen 10 min G, et al: Effect of supplemental nocturnal oxygen on
TcPCO2
SaO2 (%) 90
gas exchange in patients with severe obstructive lung
disease. N Engl J Med 1984;310:425429.
TcPCO2 (mm Hg) 80
SaO2
70

TABLE 226
Eucapnic and Hypercapnic Patients with Overlap
Syndrome Healthy
3-5%
STUDY #1 STUDY #1 STUDY #2
Peak flow
OLS OLS OLS
Baseline
EUCAPNIC HYPERCAPNIC HYPERCAPNIC
(N = 14) (N = 14) (N = 7)
FEV1 (liters) 1.01 1.12 2.03 (61%
Nocturnal
pred) 15-20% asthma
FEV1/FVC 0.44 0.47 0.61
4 PM 4 AM
PaO2 71 60 52 Time
(mm Hg)
FIGURE 2217 Both healthy individuals (solid line) and subjects with nocturnal
PaCO2 40 50 51
asthma (dotted line) have circadian alterations in lung function with nadirs occurring at
(mm Hg)
approximately 4 AM. The circadian variation in lung function is increased in subjects with
NREM AHI AHI 40 51 57 (AHI NREM nocturnal asthma and might exceed 20% over the course of the 24-hour period. From
+ REM) Sutherland ER: Nocturnal asthma. J Allergy Clin Immunol 2005;116:11791186.
Lowest SaO2 85 77 no data
AHI = apnea-hypopnea index; FEV1 = forced expiratory volume in 1 second; BOX 224
FVC = forced vital capacity; NREM = non-rapid eye movement; OLS = overlap
syndrome; PaCO2 = arterial partial pressure of carbon dioxide; PaO2 = arterial Manifestations of Nocturnal Asthma
partial pressure of oxygen; REM = rapid eye movement; SaO2 = arterial
oxygen saturation. Morning drop in FEV1 > 15% (often 1550%)
Study #1 Chan CS, Grunstein RR, Bye PT, et al: Obstructive sleep apnea with Increased circadian variation in FEV1
severe chronic airflow limitation. Am Rev Respir Dis 1989;140:12741278. Decreased response to bronchodilators during early AM
Study #2 Bradley TD, Rutherford R, Lue F, et al: Role of diffuse airway
Increased bronchial hyperresponsiveness to methacholine
obstruction in the hypercapnia of obstructive sleep apnea. Am Rev Respir Dis
1986;134:920924. Nocturnal awakenings with symptoms of asthma
FEV1 = forced expiratory volume in 1 second.

ASTHMA
Nocturnal asthma is usually defined as occurring in patients
with a 15% or greater drop in the peak flow (or FEV1)
between bedtime and morning awakening.53,54 Even normal
persons have a circadian variation in lung function with
the best function around 4 PM and the worst at 4 AM.
However, the variation is much greater in patients with
asthma. Asthmatic patients can experience a 20% to 50%
drop in the FEV1 from bedtime until morning (morning
dippers) (Fig. 2217). The overnight drop in lung func-
tion is also associated with airway hyperresponsiveness,
increasing airway inflammation, and a decreased response
to inhaled bronchodilators.5457 Some of the manifestations
of nocturnal asthma are listed in Box 224.
Important considerations for the diagnosis and treatment
of nocturnal asthma are listed in Box 225.
Epidemiology
The largest study of the prevalence of nocturnal asthma was
reported by Turner-Warwick in 198858 and surveyed 7729
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422 Chapter 22 Sleep and Obstructive Lung Disease
BOX 225
Diagnosis and Treatment of Nocturnal Asthma
1. The degree of diurnal variation in airflow can most easily
be documented by peak flow measurements at bedtime
and on awakening.
2. When OSA is present in asthmatic patients, adequate
treatment of OSA may improve the asthma.
3. The addition of a long-acting bronchodilator is indicated
if patients with nocturnal asthma do not respond to
inhaled steroids or if the required dose of inhaled
steroids is higher than desired.
4. Long-acting inhaled beta agonists taken at bedtime
have been shown to improve morning flow rates as well
as, if not better than, theophylline and may improve
perceptions of sleep quality more than theophylline in
some patients.
5. If theophylline is used for nocturnal asthma, dosing
should be such that the highest levels are during the
night or the early morning hours.
6. Treatment of GER does not appear to improve asthma in
patients who do not complain of GER symptoms.
Treatment of GER is indicated in symptomatic patients
(complain of GER symptoms).
GER = gastroesophageal reflux; OSA = obstructive sleep apnea.
asthmatics. The study revealed that 74% woke up at least
once each week with asthma symptoms and 65% woke up
with symptoms at least 3 times/wk. In those who considered
their asthma mild, 26% woke up every night with symp-
toms of asthma. The majority of respiratory arrests or sudden
death occurred from midnight to 8 AM.59 The presence and
frequency of nocturnal asthma (nocturnal awakening) is
one of the criteria for determining the severity of asthma.
Persistent mild, moderate, and severe asthma are character-
ized by nocturnal awakenings 3 to 4 times/mo, more than
once weekly but not nightly, and usually 7 times/wk, respec-
tively (Expert Panel Report 3, National Heart, Lung, and
Blood Institute PR3, http://www.nhlbi.nih.gov/guidelines/
asthma/asthgdln.pdf).
Etiology of Nocturnal Asthma
The etiology of this circadian variation is likely multifactorial
with a number of proposed mechanisms (Box 226). These
include circadian changes in the amounts of circulating ste-
roids, cathecholamines, and inflammatory mediators in the
lungs as well as a nocturnal increase in cholinergic tone.56,60
Studies of infusions of adrenaline61 or administration of
high-dose steroids62 were not able to eliminate the circadian
variation in bronchomotor tone. The relative role of other
circadian rhythms and sleep in causing nocturnal worsening
of asthma has been controversial. One study found the dip
in peak flow moved to the daytime sleep period in shift
workers.63
Sleep also appears to have an adverse effect on asthma,
independent of other factors. Ballard and colleagues20 found
BOX 226
Possible Causes of Circadian Variation in Asthma
Increased nocturnal parasympathetic (vagal) tone
Decreased circulating cortisol and epinephrine
Influx of inflammatory cells into the lung
Nocturnal gastroesophageal reflux
Allergen exposure (bed mites, dust)
Obstructive sleep apnea (snoring)
Adverse effect of sleep (controlling for time of day and
body position)
that sleep increased lower airway resistance by comparing
supine nighttime changes between asthmatics and normal
individuals who either slept in the supine position or were
kept awake while supine. In asthmatics, there was a progres-
sive increase in lower airway resistance over the night (both
wake and sleep) but the increase in resistance was greater
during sleep (Fig. 2218). In another study, Ballard and asso-
ciates10 found that despite elevated lung volumes during
wakefulness, the FRC of asthmatics had a larger than normal
drop during sleep with the lowest levels during REM. The
FRC was lower during REM compared to NREM sleep (see
Fig. 227).
Airway Inflammation
Kraft and coworkers64 found the biopsy of the small airway
at 4 AM showed differences in the number of eosinophils per
unit volume in asthmatics with nocturnal asthma compared
with patients with non-nocturnal asthma. No differences in
eosinophils were found in the large airways. In nocturnal
asthma patients, there were more alveolar eosinophils at 4
AM than at 4 PM. A later study by the same group found that
CD4+ lymphocytes (important for eosinophil recruitment)
were increased in alveolar tissue at night in nocturnal asthma
but not in asthmatic patients without nocturnal asthma.65
Kelly and colleagues66 investigated circadian changes in
airway inflammation in patients with mild atopic asthma
(mean FEV1 93% of predicted). In this patient population,
bronchoalveolar lavage (BAL) fluid contained increased
numbers of macrophages, neutrophils, and CD4+ T lympho-
cytes at 4 AM versus 4 PM. In addition, the percentage of
CD4+ T lymphocytes in the 4 AM lavage fluid was inversely
correlated with the 4 AM FEV1.
Melatonin
Melatonin, a hormone secreted by the pineal gland at night
(in darkness), has proinflammatory effects. The addition of
melatonin to zymosan stimulation of peripheral blood
monocytes increased the production of interleukin-1 (IL-1),
IL-6, and tumor necrosis factor-alpha (TNF-alpha) when
compared with zymosan stimulation alone in normal con-
trols and asthmatic patients.67 The cytokine production was
higher in patients with asthma than in normal subjects.
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 Chapter 22 Sleep and Obstructive Lung Disease 423

Higher Lower Airway Resistance

during sleep compared to awake
60 (both supine, same time of night) 60

50 50
Asthma Normal
Rla (cm H2O/L/sec)

Rla (cm H2O/L/sec)

40 40
No effect sleep vs wake

30 30

20 20

10 10

0 0
0000 0100 0200 0300 0400 0500 0600 0000 0100 0200 0300 0400 0500 0600
A Time B Time
Supine, sleep Supine, awake
Rla  lower airway resistance

FIGURE 2218 A, In asthmatics, lower airway resistance (Rla) increased overnight during supine wake and sleep. However, during sleep, the change was greater.
B, In normal subjects, there was minimal change overnight and no difference between wake and sleep. A and B, From Ballard RD, Saathoff MC, Patel DK, et al: Effect
of sleep on nocturnal bronchoconstriction and ventilatory patterns in asthmatics. J Appl Physiol 1989;67:243249.

NOCTURNAL ASTHMA Factors Worsening Nocturnal Asthma

0
r  0.79 Allergens in the Bedroom
5 P  .036 The importance of allergens in the bedroom is controversial.
Woodcock and associates69 were not able to find a benefit
Overnight change in FEV1 (%)

10
from having patients use allergen-impermeable bed covers.
15 It still seems prudent to minimize exposure to allergens if
20 possible.

25 Gastroesophageal Reflux

30
35
40
45
20 40 60 80
Melatonin (pg/mL)
FIGURE 2219 Inverse correlation between peak serum melatonin level and
percentage overnight change in forced expiratory volume in 1 second (FEV1) in subjects
with nocturnal asthma. From Sutherland ER, Ellison MC, Kraft M, et al: Elevated serum
melatonin is associated with the nocturnal worsening of asthma. J Allergy Clin Immunol
2003;112:513517.
Another study found that melatonin levels are higher in
patients with nocturnal asthma than in both asthmatic
patients without nocturnal asthma and healthy control
subjects.68 In subjects with nocturnal asthma, there was an
inverse correlation between melatonin level and overnight
decrease in lung function (Fig. 2219). The clinical impor-
tance of the effects of melatonin on asthma remains to be
determined. Other studies are needed to confirm these
results.
Several studies have supported the idea that gastroesopha-
geal reflux (GER) may worsen asthma. Studies have shown
that GER as defined by abnormal esophageal pH monitoring
can occur in 62% of patients without GER symptoms.70
Harding and coworkers71 treated 22 patients with both
asthma and GER (documented by 24-hr pH monitoring) for
100 120
3 months with doses of omperazole documented to normal-
ize 24-hour pH monitoring. Seventy-three percent of the
patients had improvement in either asthma symptoms (67%)
or peak expiratory flow (20%). Cuttitta and colleagues72
investigated the relationship of reduced esophageal pH (evi-
dence of GER) and lower airway resistance. The most impor-
tant predictor of an increase in lower airway resistance was
the duration of esophageal acid contact. However, studies
have not conclusively shown that treatment of GER will
improve asthma. A systematic review published in 2001 con-
cluded that treatment of GER does not improve asthma.73 A
parallel-group, randomized, double-blind study of esomp-
erazole for treatment of poorly controlled asthma (patient
did not complain of GER) found no difference in episodes
of asthma exacerbations between placebo and esomperazole
groups.74 GER was found in 40% of patients using pH moni-
toring (asymptomatic). No subgroup of patients could be
identified in which treatment of GER improved asthma. The
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424 Chapter 22 Sleep and Obstructive Lung Disease

investigators concluded the GER is unlikely to be a major
factor in uncontrolled asthma. However, this group of
patients did not have GER symptoms. Treatment of patients
with asthma and GER could be considered (for GER alone)
but may also help asthma in individual patients. However,
there is no evidence that treatment of GER in patients with
intractable asthma without symptomatic GER is of benefit.
OSA/Obesity
If OSA is present in patients with asthma, treatment with
nasal CPAP can improve the asthma. Chan and associates75
treated patients with both OSA and asthma and found that
the peak expiratory flow rate improved in the morning and
night after 2 weeks of treatment. In another study, weight
loss in a group of obese asthmatics improved pulmonary
function.76
Diagnosis of Nocturnal Asthma
The easiest way to diagnose severe nocturnal worsening of
asthma is to have the patient record peak flow measurements
at bedtime and upon awakening. Although there is not a
widely accepted criteria, a fall in the peak flow of greater than
15% (evening to awakening) supports the diagnosis of noc-
turnal asthma.
Chronotherapy
Chronotherapy is the design of treatment to respond to cir-
cadian changes in disease. If theophylline is used, dosing so
that the peak level will occur in the early morning may
improve effectiveness. Martin and coworkers77 compared
twice-daily sustained-release theophylline versus once-daily
sustained-release theophylline in subjects with nocturnal
asthma and demonstrated that administration of the once-
daily preparation at 7 PM resulted in a higher serum theoph-
ylline concentration at night than did an equivalent dose of
the twice-daily preparation given at 7 PM and 7 AM. The 7 AM
FEV1 was higher in subjects who received the once-daily
preparation. The dosing of oral78 or inhaled steroids79 at 3 to
4 PM appears to have a greater effect on nocturnal asthma. A
double-blind, placebo-controlled study evaluated the effects
of a 50-mg oral dose of prednisone given at 8:00 AM, 3:00 PM,
or 8:00 PM on overnight spirometry, blood eosinophil counts,
and BAL cytology in seven individuals who had asthma.79 A
single prednisone dose at 3:00 PM resulted in a reduction in
the overnight percentage decrease in FEV1 and improvement
in the FEV1 measured at 4:00 AM. In contrast, neither the 8:00
AM nor the 8:00 PM prednisone dose resulted in overnight
spirometric improvement. After the 3:00 PM prednisone
dose, blood eosinophil counts were also significantly reduced
at both 8:00 PM and 4:00 AM. These findings have not altered
the usual clinical practice of administering oral steroids in
the morning.
Treatment of Nocturnal Asthma
Important treatment considerations for nocturnal asthma
are listed in Box 225, and general asthma guidelines (Step
treatment) are listed in Table 227. Reducing the burden of
allergen exposure by keeping the bedroom free of dust may
help. The foundation of treatment of chronic persistent
asthma is inhaled corticosteroids. Weersink and colleagues80
studied a group with nocturnal asthma and patients were
treated with inhaled fluticasone, salmeterol (a long-acting
beta agonist [LABA]), or the combination. The three treat-
ments all reduced the circadian variation in peak flow
to less than 10% (Fig. 2220), improved the bronchial

TABLE 227
Guidelines for Asthma Management
INTERMITTENT
ASTHMA PERSISTENT ASTHMA
STEP 6
STEP 5 Preferred:
High-dose ICS +
STEP 4 Preferred:
LABA + oral
High-dose ICS + LABA
STEP 3 Preferred: corticosteroid
And
Medium-dose ICS And
STEP 2 Preferred: Consider omalizumab
+ LABA Consider omalizumab
Low-dose ICS + LABA for patients who
STEP 1 Preferred: Alternatives: for patients who
Or have allergies
Low-dose ICS Medium-dose ICS have allergies
Preferred: Medium-dose
Alternatives: + either LTRA,
SABA prn ICS
Cromolyn, LTRA, theophylline, or
Alternatives:
nedcromil, or zileuton
ICS + either LTRA,
theophylline
theophylline, or
zileuton
ICS = inhaled corticosteroid; LABA = long-acting beta agonist; LTRA = leukotriene receptor antagonist; SABA = short-acting beta agonist.
Adapted from Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood InstituteNational Asthma
Education and Prevention Program. Available at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf
DaneshGroup.com

Salmeterol
60
55
50
Circadian variation in PEF (median, range)
45
40
35
30
25
20
15
10
Before After
hyperresponsiveness to methacholine both day and night,
and improved cognitive performance during daytime testing.
Thus, the usual practice is to start with inhaled steroids and
add a long-acting inhaled beta agonist if symptoms persist
(see Table 22-7).
Both inhaled long-acting beta agonists and sustained-
action theophylline preparations have been effective in treat-
ment of nocturnal asthma.77,8184 Selby and associates82 found
only a slight advantage for salmeterol compared with the-
ophylline in sleep quality (fewer arousals). The falls in
morning flow rates were similar but awakenings were less
frequent on salmeterol. Weigand and coworkers83 found sal-
meterol to be more effective than theophylline at preventing
the morning drop in flow rates. The drugs did not differ in
PSG findings, but patients perceived better sleep with salme-
terol than with theophylline. In any case, the long-acting
beta agonists require less attention to dosing than theophyl-
line. Whereas asthmatics generally have a greater response
to beta agonists than anticholinergic medications, vagal tone
is increased at night. Therefore, one might expect that
inhaled anticholinergics might be helpful. There is evidence
that the addition of an inhaled anticholinergic to standard
treatment may be helpful in some patients with moderate to
severe asthma.84A recent study85 documented the effective-
ness of the addition of tiotropium (long-acting anticholiner-
gic) to patients still not well controlled with an inhaled
steroid. This approach may provide an alternative to long-
acting beta agonists or an additional treatment if the combi-
nation of inhaled steroids and a long-acting beta agonist is
unable to control nocturnal symptoms.
Although theophylline could have stimulatory effects and
impair sleep, this possible side effect is probably outweighed
by benefit from bronchodilator effects in some patients. As
Chapter 22 Sleep and Obstructive Lung Disease 425
Fluticasone Salmeterol  fluticasone FIGURE 2220 Effects of three treatment regimens on the
variability in peak expiratory flow (PEF) over the night. All three
were effective. From Weersink EJM, Douma RR, Postma DS, et al:
Fluticasone propionate, salmeterol xinafoate, and their
combination in the treatment of nocturnal asthma. Am J Respir
Crit Care Med 1997;155:12411246.
Before After Before After
noted previously, if theophylline is used, the dosing should
be altered so levels are relatively high at night. Because of the
need to follow theophylline levels and adjust the dose to both
obtain optimal treatment and avoid serious toxicity, long-
acting beta agonists are favored by most clinicians. If there
are symptoms of nocturnal GER, treatment with a proton
pump inhibitor may improve asthma in some patients. The
evening proton pump inhibitor should be given before the
evening meal rather than at bedtime. If sleep apnea is present,
treatment with CPAP may improve asthma in some patients.75
CLINICAL REVIEW QUESTIONS
1. A 50-year-old man with moderate COPD has a room air
blood gas showing a PaO2 of 60 mm Hg. He undergoes
nocturnal oximetry that reveals 200 minutes with an SaO2
less than 88%. There are long periods in which the average
SaO2 is around 85%. A saw-tooth pattern is seen in about
half of the tracing. The patient reports snoring but no
daytime sleepiness. What do you recommend?
A. Treatment with supplemental oxygen at 2 L/min.
B. Treatment with supplemental oxygen at 2 L/min and
repeat the oximetry.
C. PSG.
D. Addition of an inhaled long-acting beta agonist and
repeat the oximetry.
2. Which of the following is (are) mechanisms of nonapneic
(hypopneic) NOD during REM sleep?
A. Low baseline SaO2.
B. Intercostal muscle hypotonia.
C. Hypoventilation.
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426 Chapter 22 Sleep and Obstructive Lung Disease
  mismatch.
D. V/Q
E. All of the above.
3. Which of the following is thought to play a role in the
morning fall in the FEV1 in asthma patients?
A. High cortisol levels at night.
B. High circulating catecholamines.
C. Increased inflammatory cells in the lung.
D. Low parasympathetic tone.
4. Which of the following are predictive of significant arte-
rial oxygen desaturation during sleep in a patient with
COPD?
A. Daytime PaCO2 = 55 mm Hg.
B. Pink puffer COPD type.
C. Blue bloater clinical type.
D. Daytime PaO2 = 70 mm Hg.
E. A and C.
F. B and D.
5. In spirometry, which of the following is used to assess the
severity of COPD (GOLD criteria)?
A. FEV1 (% predicted).
B. FVC (% predicted).
C. FEV1/FVC (% predicted).
D. Postbronchodilator FEV1 (% predicted).
E. Postbronchodilator FVC (% predicted).
6. A 30-year-old patient with known intermittent asthma
has begun to develop awakenings with dyspnea and
cough twice weekly. The evening peak flow is 450 L/min
and that on awakening in the morning is 350 L/min. The
patient has been using a short-acting beta agonist inter-
mittently. What do you recommend?
A. Short-acting beta agonist at bedtime.
B. Long-acting beta agonist at bedtime.
C. Inhaled corticosteroids.
D. Inhaled corticosteroids and long-acting beta agonist
at bedtime.
Answers
1. C. Although the patient may well require supplemental
oxygen as a component of therapy, the presence or
absence of OSA must be determined. The saw-tooth
pattern suggests sleep apnea is present and that the patient
has OLS. Optimal therapy includes treatment of both
OSA and COPD.
2. E.
3. C. Increased inflammatory cells appear to enter the
airways and lung. Cortisol and circulating catecholamine
levels are lower during the night and parasympathetic
tone is higher during sleep.
4. E. Worse nocturnal SaO2 is predicted by a lower daytime
SaO2/PaO2, hypercapnia, and the blue bloater clinical
type.
5. D.
6. C. The patient has nocturnal asthma evidenced by a 22%
fall in the peak flow as well as symptoms. The treatment
of choice is inhaled corticosteroids. If this is not effective,
the addition of a long-acting beta agonist is the next step.
However, the patient may improve with inhaled cortico-
steroids alone.
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The Restless Leg Syndrome,
Periodic Limb Movements in
Sleep, and the Periodic Limb
Movement Disorder
Chapter Points
A diagnosis of the RLS is based on clinical history. The
essential elements include URGE (Urge to move, Rest
makes symptoms worse, Gets better with movement
temporary improvement in symptoms with movement,
and Evening is worse [symptoms worse in the evening,
at least at the onset of the syndrome]).
Supportive clinical features for the diagnosis of
RLS include a family history, improvement with
dopaminergic treatment, and the presence of PLMS
on PSG.
Secondary causes of RLS included renal failure,
pregnancy, iron deficiency, and medications.
Medications frequently worsening RLS include
first-generation antihistamines, antidepressants
(except bupropion), and dopamine blockers
(phenothiazines, metochlopramide).
A diagnosis of PLMD is based on both history and
PSG findings: (1) A complaint of sleep disturbance
or daytime fatigue, (2) PSG findings PLMSI > 5/hr
(children) and > 15/hr in adults, (3) Symptoms are not
better explained by another sleep, medical, or
neurologic disorder, or medication use (e.g., OSA). A
diagnosis of RLS excludes a diagnosis of PLMD. A
complaint of sleep disturbance must be made by the
patient (in contrast to the bedmate).
PLMS is a PSG finding. PLMS is very common in older
adults and is most often asymptomatic. PLMS can be
associated with OSA, narcolepsy, and RBD.
About 80% of patients with RLS will have a PLMS index
5/hr on PSG.
The PLMD may precede a diagnosis of RLS in children.
A diagnosis of RLS is difficult in children because they
Chapter 23
may not report traditional symptoms. They may
present with growing pains.
Treatment options for RLS include conservative
measures, dopaminergic medications (LD/CD and
DAs), anticonvulsants, opiates and opioid agonists, and
sedative hypnotics.
LD/CD is a rapidly absorbed dopaminergic medication
(LD is a precursor of dopamine) that is effective
treatment of RLS. It is a good option for intermittent
RLS. However, the medication has a short duration
of action and continued use results in augmentation
in up to 80% of cases (especially with doses of LD
> 200 mg daily).
The DAs ropinirole and pramipexole are FDA
approved for treatment of RLS in adults and are
considered the treatment of choice for daily RLS.
They must be given 2 hours before symptoms to
be most effective.
Anticonvulsants are also effective for RLS/PLMD.
Due to a good safety profile, gabapentin is the
anticonvulsant recommended for RLS treatment. Doses
of 900 to 1500 mg of gabapentin may be needed to be
effective. A slow upward titration of the dose starting
at 300 mg may improve tolerance to use. Gabapentin
is considered a first-line medication by some clinicians
if RLS is associated with pain.
Narcotics are effective treatment for RLS. They may be
especially useful in patients who develop
augmentation or do not tolerate DAs. If given only at
bedtime, they usually do not result in dependence. For
milder cases, codeine, propoxyphene, or tramadol may
be effective. For moderate RLS, hydrocodone
(combined with acetaminophen in the United States)
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430 Chapter 23 The RLS, PLMS, and the PLMD

PSG.12 The percentage of patients with PLMS who have RLS

or oxycodone is often used. For severe RLS, oxycodone
has not been well-defined, but the vast majority of patients
or methadone has been used with success.
with PLMS do not have RLS. PLMS has been associated with
Sedative hypnotics may be useful in milder RLS
narcolepsy, the REM sleep behavior disorder, and obstruc-
associated with insomnia or can be combined with
tive sleep apnea (OSA). A diagnosis of RLS excludes PLMD.
other classes of medications. Most of the published
PLMS is very common, RLS is common, and PLMD is
treatment trials used clonazepam (long half-life), but
thought to be rare. Chapter 12 outlines the scoring criteria
other BZRAs may also be effective.
for PLMS in detail with examples of illustrative tracings. This
Augmentation describes a phenomenon that is
chapter emphasizes the clinical significance of PLMS.
characterized by one or more of the following: (1)
earlier symptom onset, (2) greater severity of
symptoms at the same dose/or escalating dose, (3) RESTLESS LEGS SYNDROME
reduced latency to onset of symptoms with rest, and
The RLS is a common disorder often underdiagnosed and
(4) spread of symptoms to involve new body parts
improperly treated. In 1995, the International Restless Legs
(arms as well as legs).
Syndrome Study Group (IRLSSG)11 published a statement on
Low serum ferritin (<45 to 50 g/mL) is a risk factor
for development of augmentation.
RLS patients with a ferritin less than 45 to 50 g/mL
may improve with iron supplementation. The usual 40
dose is ferrous sulfate 325 mg tid with each dose given
with 100 to 200 mg of ascorbic acid to improve
absorption. Patients with augmentation may improve 30
PLMS index (#/hour)
with iron supplementation.

20

The restless legs syndrome (RLS), periodic limb movements

in sleep (PLMS), and the periodic limb movement disorder 10
(PLMD) are three distinct but related entities16 (Table 231).
A diagnosis of RLS is based on clinical history. PLMS is a
polysomnography (PSG) finding that may or may not be 0
clinically important. The PLMD is diagnosed in patients 5-9 10-19 20-29 30-39 40-49 50-59 >60
with PLMS on PSG who have a sleep complaint (sleep-onset Age groups
or maintenance insomnia or, less commonly, daytime sleepi- FIGURE 231 Mean periodic limb movements in sleep (PLMS) index (# events/hr of
ness) not better explained by another sleep disorder.6 PLMS sleep) at different ages for normal healthy individuals. The average PLMS index increases
is a very common finding especially in older patients (Fig. in older individuals. Error bars are SEM. From Pennestri M, Whittom S, Adam B, et al:
231) and is often asymptomatic.5,711 Approximately 80 to PLMS and PLMW in healthy subjects as a function of age: prevalence and interval
90% of patients with RLS will have findings of PLMS on distribution. Sleep 2006;29:11831187.

TABLE 231
Different Leg Movement Conditions
RLS PLMS PLMD
Diagnosis History PSG PSG + History
Prevalence Common Very common Rare
Asymptomatic individuals
Narcolepsy
REM sleep behavior disorder
OSA
Associated findings 80% have PLMS Usually asymptomatic or Must exclude other
symptoms are not due to PLMS causes of insomnia or
A minority of patients have RLS daytime sleepiness
Relationship with other leg A diagnosis of RLS excludes a A PSG finding not a disorder Not diagnosed if RLS is
movement conditions diagnosis of PLMD present
OSA = obstructive sleep disorder; PLMD = periodic limb movement disorder; PLMS = periodic limb movement in sleep; PSG = polysomnography; REM = rapid eye
movement; RLS = restless leg syndrome.
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BOX 231
Diagnostic Criteria for Restless Legs Syndrome
A. The patient reports an urge to move the legs, usually
accompanied or caused by uncomfortable and
unpleasant sensations in the legs.
B. The urge to move or unpleasant sensations begin or
worsen during periods of rest or inactivity such as
lying or sitting.
C. The urge to move or unpleasant sensations are partially
or totally relieved by movement, such as walking or
stretching, as long as the activity continues.
D. The urge to move or sensations are worse, or only occur,
in the evening or night.
E. The condition is not better explained by another current
sleep disorder, medical or neurologic disorder,
medication use, or substance use disorder.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
the primary and associated features of the syndrome. The
criteria were refined during a workshop at the National Insti-
tutes of Health (NIH).13 The criteria form the basis for the
International Classification of Sleep Disorders, 2nd edition
(ICSD-2) diagnostic criteria for RLS6 (Box 231). There are
four essential diagnostic criteria for RLS (URGE = urge to
move, rest induced, gets better with activity, evening and
night worse).
The Essential RLS Diagnostic Criteria6,13
1. The patient reports an urge to move the legs, usually
accompanied or caused by uncomfortable and unpleasant
sensations in the legs. Of note, the urge to move can be
present without associated symptoms. Commonly
reported RLS sensations are listed in Box 232. Although
called the restless legs syndrome, symptoms can occur
in the arms as well as the legs in 30% to 50% of the
patients.12,13 Although RLS symptoms are usually bilat-
eral, some patients report symptoms mainly in one
extremity.12 About 20% of RLS patients report the leg
sensations to be painful. Involuntary leg movements
may also be reported without an urge to move (the legs
just move on their own). As discussed later, this is a
manifestation of periodic limb movements during wake
(PLMW).
2. RLS symptoms begin or worsen during periods of inactiv-
ity such as lying or sitting. Being stationary and having
decreased mental activity appear to both worsen
symptoms.
3. The urge to move or unpleasant sensations are totally or
partially relieved by movements such as walking or
stretching as long as the activity continues (temporary
relief). Rubbing the legs or taking hot or cold baths may
improve symptoms in some patients. Of note, increased
Chapter 23 The RLS, PLMS, and the PLMD 431
BOX 232
Abnormal Sensations in Restless Legs Syndrome
COMMON PATIENT DESCRIPTIONS OF SENSATIONS
Creepy, crawly.
Ants crawling under the skin.
Worms crawling in the veins.
Pepsi-Cola in the veins.
Nervous feet gotta move.
Itching under the skin, itchy bones.
Crazy legs/Elvis legs.
Toothache feelingcant leave it alone.
Excited nerves, electric-like shocks.
CHARACTERISTICS OF SENSATIONS
Daytime symptoms if RLS is severe.
If RLS very severe, symptoms may not be worse at night.
Usually bilateral but can be unilateral.
Arms may be involved in 3050%.
Sensations are painful in 20%.
May be absentsimply urge to move.
RLS = restless legs syndrome.
mental activity or eating can improve the symptoms
(popcorn therapy while watching a movie).
4. The urge to move or unpleasant sensations are worse in
the evening or night. If RLS has become very severe,
nocturnal worsening may not be reported but should
have been present earlier in the disease course. When
RLS is severe, daytime symptoms can occur especially
during periods of inactivity.
Supportive Clinical Features
Some patients will report atypical symptoms.13 The support-
ive clinical features of RLS (Box 233) may help resolve
diagnostic uncertainty. They are not required for a diagnosis
of RLS. In studies of groups of patients with RLS, a familial
history is reported in 50% to 60% of the cases. A family
history of RLS is supportive of the diagnosis. An improve-
ment with a trial of dopaminergic treatment is also evidence
that symptoms represent the RLS. However, one must be
aware of the placebo effect. Placebo-controlled studies in
RLS report considerable improvement in symptoms with
inactive medication. The periodic limb movements in sleep
index (PLMSI) is defined as the number of periodic limb
movements (PLMs) per hour of sleep. The criteria for scoring
a leg movement as a periodic leg movement are discussed in
Chapter 12. It is difficult to define a normal PLMSI (see Fig.
231). In the past, some sleep centers considered a PLMSI
of 5/hr or greater to be abnormal. However, many asymp-
tomatic individuals have much higher PLMSI values,79 The
presence of PLMS can provide supporting evidence for the
presence of the RLS. One study employing a PLMSI cutoff
of 5/hr reported that 80.2% of patients with RLS had PLMS
(87% if 2 nights were monitored).12 Patients with RLS often
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432 Chapter 23 The RLS, PLMS, and the PLMD

BOX 233 report repetitive involuntary leg movements during wakeful-

Supportive Clinical Features of Restless ness when at rest especially at night. This is a manifestation
Legs Syndrome of PLMW (periodic limb movements during wake).

FAMILY HISTORY Differential Diagnosis of RLS/PLMS

The prevalence of RLS among first-degree relatives of
patients with RLS is 3 to 5 times greater than in people
without RLS.
5060% of patients with RLS report a family member with
RLS.
RESPONSE TO DOPAMINERGIC THERAPY
Nearly all patients with RLS show at least an initial
positive therapeutic response to either L-dopa or a
dopamine receptor agonist at doses considered low
compared with those used to treat Parkinsons disease.
PERIODIC LIMB MOVEMENTS (DURING WAKEFULNESS
OR SLEEP)
Involuntary movements during wake or sleep.
PLMS occur in at least 80% of patients with RLS
however, PLMS commonly occur in other disorders and in
the elderly.
PLMW is a manifestation of RLS.
PLMS = periodic leg movements in sleep; PLMW = periodic leg movements
during wake; RLS = restless legs syndrome.
Adapted from Allen RP, Picchietti D, Hening W, et al. Restless legs syndrome:
diagnostic criteria, special considerations, and epidemiology. A report from
the Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the
National Institutes of Health. Sleep Med 2003;4:101119.
The differential diagnosis of RLS/PLMS includes a number
of mimics1316 (Table 232 and Box 234). Most of these are
not associated with an urge to move. Often, the movements
are not worse at night and symptoms are not temporarily
improved by movement.
Hypnic jerks are usually single, whole body jerks that occur
at sleep onset. They are not associated with abnormal
sensations.
Neuropathy may present as pain and/or burning in the legs
or feet but is usually associated with an abnormal neuro-
logic examination and is not associated with an urge to
move. Neuropathic pain is usually not improved with
movement or rubbing. The pain may be worse at night
but is usually present during the day. RLS and neuropa-
thy can exist together.
Positional discomfort is associated with a need to move in
bed to relieve pressure that compresses nerves, limits
blood flow, or stretches tissue. The sensations may be
painful but are improved with change in position rather
than with movement.
Neuroleptic akathisia is characterized by involuntary move-
ment of the face or extremities (such as body rocking,

TABLE 232
Characteristics of Restless Legs Syndrome Mimics
URGE TO ABNORMAL WORSE IN THE IMPROVED BY NEUROLEPTIC
MOVE SENSATIONS EVENING/NIGHT MOVEMENT NEUROLOGIC STUDIES USE
RLS Yes Usually Always Temporary Neurologic examination No
improvement usually normal, EMG
often normal
Hypnic jerk No No Sleep onset Single whole body Normal No
jerk
Neuropathy No Yes, can be Sometimes No Decreased sensation, No
painful abnormal EMG/nerve
conduction
Positional Yes Usually Usually Change in position Variable No
discomfort not movement
Neuroleptic Inner No Not usually Not usually Variable YES
akathisia restlessness
Leg cramps No Pain localized Sometimes Stretching not Normal No
to muscle movement
Claudication No Pain Not usually Walking may Decreased pulses No
worsen
Painful toes, No Pain, burning Not usually No Abnormal EMG, MRI may No
moving leg show lumbosacral
syndrome nerve compression
EMG = electromyogram; MRI = magnetic resonance imaging; RLS = restless legs syndrome.
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BOX 234
Differential Diagnosis of Restless Legs Syndrome
and Periodic Limb Movements in Sleep
Hypnic jerkswhole body jerks at sleep onset,
involuntary, no urge to move.
Positional discomfortneed to move in bed to relieve
pressure that compresses nerves, limits blood flow, or
stretches tissue.
Sleep-related leg crampsmuscle hardening and pain of
specific muscle groups, tenderness and sensitivity remain
after cramping subsides, stretching more than movement
provides relief.
Neuroleptic akathisiageneralized nature of need to
move the body and the occurrence in association with use
of dopamine receptor antagonists (phenothiazines,
metaclopramide).
Painful legsmoving toes syndromepain in the lower
limbs with spontaneous movements of the toes or feet. The
pain is most often burning and the movements consist of
flexion/extension, abduction/adduction, fanning, or
clawing of the toes, fingers, foot, or hand. Painless variants
exist. Causes include nerve root lesions, herpes zoster, HIV,
neuroleptics, chemotherapeutic agents, peripheral trauma,
and polyneuropathy for alcoholism.
HIV = human immunodeficiency virus.
marching in place, or movement of the extremities) and
is NOT worse during the night or at rest. There is invari-
ably a history of use of neuroleptics (phenothiazines)
and other dopamine blockers (metoclopramide). The
movements are associated with inner restlessness but not
abnormal sensations.
The painful legsmoving toes (PLMT) syndrome13,16 is
characterized by pain in the lower limbs with spontaneous
movements of the toes or feet. Variants of PLMT that are
painless or involve the arms and hands also exist. The pain
is most often burning in nature and commonly precedes
spontaneous movements consisting of flexion/extension,
abduction/adduction, fanning, or clawing of the toes,
fingers, foot, or hand. Causes of PLMT include nerve root
lesions, herpes zoster, human immunodeficiency virus
(HIV), neuroleptics, chemotherapeutic agents, peripheral
trauma, and polyneuropathy from alcoholism.
Nocturnal leg cramps are associated with localized severe
pain and tightness in a muscle. These are improved with
stretching but not just movement.
Claudication may be associated with pain even at rest, if
severe, but is usually NOT improved with movement.
Usually, claudication symptoms are worse with exertion.
Causes of RLS
Common causes of RLS are listed in Box 235. RLS is often
divided into primary RLS (independent of other disorders)
and secondary RLS (due to an identifiable cause such as a
Chapter 23 The RLS, PLMS, and the PLMD 433
BOX 235
Causes of Restless Legs Syndrome
PRIMARY RLS
Familial
Idiopathic
Characteristics
Earlier age of onset and slower progression
Familial occurrence more likely
SECONDARY RLS
Iron deficiency
Low normal ferritin level (<4550 g/L) is related to
increasing severity of RLS even if hemoglobin is
normal
Pregnancy
Neuropathydiabetic and others
Multiple sclerosis
Renal failure (transplant but NOT dialysis cures RLS)
Parkinsons disease
Medications
First-generation (sedating) antihistamines
(diphenhydramine)
Antinausea medicationprochlorperazine
Dopamine receptor blockersmetoclopramide
Antidepressants (SSRIs, SNRIs)exception is
bupropion
RLS = restless legs syndrome; SNRIs = selective serotonin and
norepinephrine reuptake inhibitors; SSRIs = selective serotonin reuptake
inhibitors.
medical disorder, condition, or medication). The cause of
primary RLS is not known. There may be an abnormality in
iron transport into the central nervous system or utilization
of iron as it relates to dopaminergic neurons. Causes of sec-
ondary RLS include renal failure, pregnancy, iron deficiency
(with or without anemia), and certain medications. Medica-
tions associated with RLS include tricyclic antidepressants,
serotonin reuptake inhibitors, dopamine blockers (pheno-
thiazines, haloperidol, metoclopramide), sedating antihista-
mines (diphenhydramine), and antinausea medications
(prochlorperazine). RLS associated with renal failure is not
helped by dialysis but is cured by renal transplantation. The
RLS of pregnancy commonly vanishes or improves with
delivery. It is prudent to check a serum iron, total iron-
binding capacity (TIBC), and ferritin in patients with RLS.
It is recommended that RLS patients have a ferritin above 45
to 50 g/mL.17 The RLS of iron deficiency may improve with
iron supplementation. If the onset of RLS can be linked to
the start of a given medication, a switch to an alternate medi-
cation can be tried. For example, bupropion is an antidepres-
sant that does not worsen RLS.18 In one study, selective
serotonin reuptake inhibitor (SSRI) medications and venla-
faxine were more likely to be associated with PLMS than
either a control group or a group taking bupropion.19 Thus,
bupropion might be less likely to cause or worsen RLS.
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434 Chapter 23 The RLS, PLMS, and the PLMD

Familial Patterns and Genetics Clinical Features of RLS

In 50% to 60% of cases of RLS, a family history of RLS can be A number of features of RLS have clinical utility (Box 236).
found.13,20 Twin studies show a high concordance rate. Most These include information about the prevalence of RLS as
pedigrees suggest an autosomal dominant pattern; however, well as variations in the presentation of RLS and symptoms
a recessive pattern with a carrier phenotype is also possible. associated with RLS.
Familial RLS has onset of symptoms at a younger age and is
more slowly progressive. The genetics of RLS, as in many
Prevalence of RLS
medical conditions, is complex2130 (Table 233). Linkage
studies have found RLS loci but no related disease-causing A number of studies have attempted to define the prevalence
sequence variants have been found. More recent genome- of RLS. The results vary considerably due to the use of
wide association studies have identified three genomic
regions MEIS1, BTBD9, and MAP2K5/LBXCOR1. In one
study, the presence of a genetic risk for the presence of PLMS BOX 236
was found whether or not RLS symptoms were present.29
Clinical Features of Restless Legs Syndrome
PREVALENCE OF RLS
Pathophysiology of RLS
510% in general population
The pathophysiology of RLS is not well understood.21,3134 Women > men
Central nervous system iron homeostatic dysregulation is
NATURAL CLINICAL COURSE
thought to be the basic mechanism. Cerebrospinal fluid
(CSF) ferritin is lower (and transferrin is higher) in RLS Can begin at any age
patients. Magnetic resonance imaging (MRI) using special RLS can be intermittent
sequencing techniques can provide measures of iron concen- Variable course
tration in specific brain regions. Using this technique, Early onset (<50 yr)onset is insidious
imaging showed reduced iron stores in the striatum and red Late onsetabrupt and more severe
nucleus.34 The dopaminergic system is also believed to be REASONS RLS PATIENTS SEEK MEDICAL ATTENTION
involved in RLS. Iron is a cofactor for the enzyme tyrosine-
Leg discomfort
hydroxylase, which is a rate-limiting step in the formation of
Sleep disturbancethe primary reason most patients
dopamine. RLS patients show a greater circadian variation
seek medical attention
in dopamine metabolites than controls. This would be con-
Sleep-onset and -maintenance insomnia
sistent with the circadian component of RLS. The current
Daytime sleepiness much less common
theory of the causation of RLS is sometimes called the iron-
RLS = restless legs syndrome.
dopamine hypothesis.

TABLE 233
Genetic Linkages and Associations in Restless Legs Syndrome
LINKAGES
AUTHOR POPULATION CHROMOSOME MODEL
22
RLS-1Desautels, 2001 French Canadian 12q Dominant
RLS-2Bonati, 200323 Italian 14q Dominant
RLS-3Chen, 200424 United States 9p Dominant
25 26
RLS-4Levchenko, 2006, 2009 French Canadian 20p Dominant
27
RLS-5Pichler, 2006 Italian 2q Dominant
ASSOCIATIONS
AUTHOR POPULATION CHROMOSOME GENE
28
Winkelmann, 2007 French Canadian/ 2p MEIS1, exon 9
European 6p BTBD9, intron 5
15q MAP2K5, LBXCOR1
Stefannson, 200729 Icelandic/US 6p BTBD9
30
Winklemann, 2007 European 12q BTBDR, intron 5
Adapted from Hening WA, Buchfuhrer MJ, Lee HB: Clinical Management of Restless Legs Syndrome. West Islip, NY: Professional Communications, 2008, pp. 5657.
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20
Any frequency
Frequency  1 /week
16
Sufferer group
Prevalance (%)
12
8
4 ON NIGHTS WHEN RLS SYMPTOMS PRESENT
0
30 31-40 41-50 51-60 61-70 >70
Age groups (years)
FIGURE 232 Prevalence of restless legs syndrome (RLS) at different age groups for
patients reporting any frequency of RLS symptoms, those reporting frequency greater
than 1/wk, and sufferers (reporting RLS symptoms 2/wk and some impact from the
symptoms when they occurred). From Hening WA, Buchfuhrer MJ, Lee HB: Clinical
management of restless legs syndrome. West Islip, NY: Professional Communications, 2008;
and Hening W, Walters AS, Allen RP, et al: Impact, diagnosis and management of restless
legs syndrome in a primary care population: the REST (RLS Epidemiology, Symptoms, and
Treatment) Primary Care Study. Sleep Med 2004;5:237246.
different RLS diagnostic criteria and different methods
(survey vs. direct patient interview).1,2,13,35,36 Approximately
5% to 10% of adults in Northern European countries report
RLS symptoms. RLS is approximately 1.5 to 2 times more
common in women than in men. However, much of the
difference in RLS prevalence between men and women is
likely due to the association of RLS with pregnancy. The
Restless Legs Epidemiology, Symptoms, and Treatment
Study (REST)35 was a large questionnaire evaluation of
23,052 primary care patients. The study found that the
overall prevalence of weekly RLS symptoms was 9.6% and
that the prevalence increased with age (Fig. 232). A large
international study of a general population (REST general
population study) found that 5% of the respondents experi-
ence RLS symptoms weekly and 2.7% reported symptoms at
least twice weekly and that the symptoms had a negative
impact on their life.36
Onset and Clinical Course of RLS
RLS can begin at any age and the clinical course is variable.
Two patterns are commonly seen (see Box 236).13 An early
onset (age < 50 yr) characterized by insidious onset, less
severity, and higher familial association. A late onset RLS
(age > 50 yr) is characterized by a more abrupt onset and
more severe manifestations. Late-onset RLS patients also
tend to have lower ferritin levels compared with early-onset
RLS patients.
Sleep Disturbance Associated with RLS
The two most common complaints that cause RLS patients
to seek medical attention are the uncomfortable leg sensa-
tions and the disturbance of sleep. Beyond the significant
discomfort caused by RLS symptoms, the disorder can cause
Chapter 23 The RLS, PLMS, and the PLMD 435
TABLE 234
Manifestation of Restless Legs Syndrome in
Restless Legs Syndrome Sufferers (N = 551)
At least one sleep-related symptom 43.4%
Consulted MD about symptoms 64.8%
Given RLS diagnosis 24.9%
>30 min to fall asleep 68.6%
3 awakenings 60.1%
RLS = restless legs syndrome.
Data from Hening W, Walters AS, Allen RP, et al: Impact, diagnosis and
management of restless legs syndrome in a primary care population: the
REST (RLS Epidemiology, Symptoms, and Treatment) Primary Care Study.
Sleep Med 2004;5:237246.
difficulty with sleep initiation and maintenance A recent
large questionnaire study of 23,052 primary care patients
identified a group of RLS sufferers (N = 551) with RLS
symptoms twice or more weekly and a negative impact from
RLS symptoms.35 In this group, 43.4% complained of sleep-
related symptoms but only 6% complained of daytime sleepi-
ness. On nights that RLS symptoms were present, 69%
complained of taking over 30 minutes to fall asleep and 60%
complained of three or more awakenings per night (Table
234). Daytime sleepiness is a less common symptom than
insomnia but can occur. In a general population study, the
prevalence of RLS of any frequency was 7.2%, weekly RLS
symptoms was 5%, and twice-weekly symptoms with dis-
tressing symptoms was 2.7%.36 Of the group with RLS twice
weekly or more, 81% had reported symptoms to primary
physicians but only 6.2% were given a diagnosis of RLS.
The etiology of sleep disturbance from RLS includes a
delay in sleep onset due to RLS symptoms. If the patient
awakens, the return to sleep may also be delayed by RLS
symptoms. Because the majority of RLS patients have PLMS,
it might be assumed that arousals associated with PLMS
contribute to sleep disturbance. However, the PLMSI
(number of PLMs/hr of sleep) is not highly correlated with
any measure of sleep disturbance in most studies of RLS
patients.12 In a study of unmedicated RLS patients, Hornyak
and coworkers37 found that the IRLSSG rating scale (IRLS)
score38,39 (RLS symptoms severity) correlated with the PLMS
arousal index but not the PLMSI. However, even the rela-
tionship between the IRLSSG rating scale (IRLS) and the
PLMS arousal index was very weak (r = 0.22, P = .03).
Medical Evaluation in RLS
The diagnostic evaluation (Box 237) should include a
history to elicit the essential and associated features of RLS.
A detailed medication history including over-the-counter
(OTC) medications (sedating antihistamines) is very impor-
tant. The IRLSSG developed a rating scale for RLS symptoms
called the IRLSSG rating scale (IRLS).38,39 A slight revision of
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436 Chapter 23 The RLS, PLMS, and the PLMD
BOX 237
Medical Evaluation of Restless Legs
Syndrome Patients
HISTORY
Presence of essential RLS criteria
RLS in family members
Neuroleptic use?
Detailed medication history (including OTC medications)
PHYSICAL EXAMINATION
Neurologicsigns of neuropathy
LABORATORY
Ferritin, TIBC, % iron saturation
Renal function
OTC = over the counter; RLS = restless legs syndrome; TIBC = total
iron-binding capacity.
the validated scale38 was published as an appendix to an
editorial.39 The IRLS is useful to quantify RLS symptom
severity and the effects of treatment (Box 238). The scale is
used in research studies but also has clinical utility in follow-
ing patients on treatment.
Physical examination should look for signs of neuropathy.
Laboratory studies should check renal and thyroid function.
A serum iron level, TIBC, % iron saturation, and ferritin
levels should be checked. The ferritin is the most useful
single test. However, ferritin can be elevated by inflamma-
tory processes. If the ferritin level is less than 45 to 50 g,
iron supplementation may improve symptoms.17 An iron
saturation less than 20% or an elevated TIBC may be useful
if the ferritin is elevated due to inflammation. PSG is NOT
required in most cases of RLS unless sleep apnea or another
sleep disorder is suspected. Of note, abnormal movements
during sleep including leg kicks can occur with OSA. If there
is a suspicion of other causes of abnormal nocturnal move-
ments such as OSA, epilepsy, sleep-related rhythmic move-
ment disorder, or the rapid eye movement (REM) sleep
behavior disorder (RBD), a sleep study is indicated. As noted
previously, daytime sleepiness is NOT a common symptom
of RLS and the presence of this symptom should prompt
consideration of disorders other than RLS. In addition, a
combination of sleep disorders, for example, RLS and sleep
apnea, is not uncommon.
PSG Findings in RLS Patients
In a study of 133 patients with RLS, it was found that the
PLMSI was greater than 5/hr in 80.2% of RLS patients.12 The
PLMSI did increase with RLS severity. There was also a sig-
nificant correlation between the PLMSI and the periodic
limb movement in wake index (PLMWI). However, there
was no correlation between PLMSI and measures of
sleep disturbance such as sleep efficiency and nocturnal
BOX 238
International Restless Legs Syndrome Study
Group Rating Scale (IRLS)Version 2.1
In the past week
1. Overall, how would you rate the RLS discomfort in your
legs or arms?
(4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
2. Overall, how would you rate the need to move around
because of your RLS symptoms?
(4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
3. Overall, how much relief of your RLS arm or leg
discomfort did you get from moving around?
(4) No relief (3) Slight relief (2) Moderate relief (1) Either
complete or almost complete relief (0) No RLS
symptoms to be relieved
4. Overall, how severe was your sleep disturbance due to
your RLS symptoms?
(4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
5. How severe was your tiredness or sleepiness due to
your RLS symptoms?
(4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
6. How severe was your RLS as a whole?
(4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
7. How often did you get RLS symptoms?
(4) Very often [67 days/wk] (3) Often [45 days/wk] (2)
Sometimes [23 days/wk] (1) Occasionally [1 day/wk]
(0) Never
8. When you had RLS symptoms, how severe were they
on average?
(4) Very severe [8 hr/24 hr] (3) Severe [38 hr/24 hr] (2)
Moderate [13 hr/24 hr] (1) Mild [<1 hr/24 hr] (0) None
9. Overall, how severe was the impact of your RLS
symptoms on your ability to carry out your daily
affairsfor example, carrying out a satisfactory family,
home, social, or work life?
(4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
10. How severe was your mood disturbance due to your
RLS symptomsfor example, angry, depressed, sad,
anxious, or irritable?
(4) Very severe (3) Severe (2) Moderate (1) Mild (0) None
RLS = restless legs syndrome.
From International Restless Legs Syndrome Study Group. Validation of the
International restless legs syndrome rating scale for the restless legs
syndrome. Sleep Med 2003;4:121122.
awakenings. Another study found a weak correlation between
the PLMS arousal index and RLS severity.37 Therefore, PLMS
does not appear to be a major cause of sleep disturbance in
most patients with RLS. The PSG is more likely to be abnor-
mal if patients with RLS complain of sleep problems (Table
235).12 In looking at the classification of RLS severity in this
table, note that the classification was influenced by sleep
complaints as well as RLS symptoms. Whereas the finding of
PLMS should always alert the clinician to the possibility of
RLS, PLMS is also common in patients with sleep apnea,
narcolepsy, and the RBD.
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TABLE 235
Polysomnography Findings in Groups with Mild,
Moderate, and Severe Restless Legs Syndrome
SEVERITY* MILD MODERATE SEVERE
N 11 38 82
Age (yr) 46.7 49.0 52.7
Sleep latency 11.7 20.2 20.2
(min)
Sleep efficiency 82.2 80.1 72.7
(%)
PLMSI (#/hr) 10.6 24.7 33.2
PLMWI 29.1 25.8 31.0
*Patients were rated as mild, moderate, or severe based on frequency and
severity of RLS complaints, severity of sleep-onset insomnia, and frequency
and duration of nocturnal awakenings.
NS = not significant; PLMSI = periodic limb movements in sleep index;
PLMWI = periodic limb movements during wake index.
From Montplasir J, Boucher S, Poirer G, et al: Clinical, polysomnographic,
and genetic characteristics of restless legs syndrome: a study of 133 patients
diagnosed with new standard criteria. Mov Disord 1997;12:6165.
RLS in Children
RLS can be difficult to diagnose in children.6,13,4043 Some
complain of typical RLS symptoms while others complain of
growing pains or simply have difficulty sitting still. The
ICSD-2 diagnostic criteria for RLS in children are shown in
Box 239. These criteria are based on the NIH workshop on
RLS, which listed criteria for probable and possible RLS for
research purposes.13 The Peds REST study found criteria for
definite RLS in 1.9% of children aged 8 to 11 years and 2%
in adolescents age 12 to 17 years.40 Of note, PLMS is less
common in children and a PLMSI of 5/hr or greater is con-
sidered abnormal. Some children with attention deficit
hyperactivity disorder (ADHD) have PLMS and possible
RLS and vice versa.44 The relationship of RLS and ADHD
remains to be determined.
PERIODIC LIMB MOVEMENTS IN SLEEP
In the earlier descriptions of PLMS, the phenomenon was
referred to as nocturnal myoclonus, but this terminology
is no longer used. As discussed in detail in Chapter 12, the
limb movements (LMs) composing PLMS are characterized
by the rhythmic repetitive stereotypic dorsiflexion/extension
of the big toe, dorsiflexion at the ankle, and sometimes
flexion at the knee and hip joints. Individual LMs that meet
criteria for PLMS are referred to as PLMs. Criteria for iden-
tifying LMs qualifying as PLMs were first proposed by
Coleman3 and later revised by a task force of the American
Academy of Sleep Medicine (AASM) in 1993.45 A revised
scoring system was published in 2006 by the World Associa-
tion of Sleep Medicine in association with the IRLSSG.46
Criteria for scoring PLMs during both sleep (PLMS) and
wake (PLMW) were published. The major change was that
Chapter 23 The RLS, PLMS, and the PLMD 437
BOX 239
Criteria for Diagnosis of Restless Legs Syndrome
in Children (Age 212 yr)
P A alone or B + C
A. The child meets all four essential adult criteria for RLS
NS and relates a description in his or her own words that is
consistent with leg discomfort.
NS
OR
.01 B. The child meets all adult criteria for RLS but does NOT
relate a description in his or her own words that is
consistent with leg discomfort.
<.05
AND
NS
C. The child has at least two of the following three
findings:
i. Sleep disturbance for age.
ii. A biologic parent or sibling with definite RLS.
iii. A PSG documented PLM index of 5/hr (5/hr of
sleep)
PLM = periodic limb movement; PSG = polysomnography; RLS = restless legs
syndrome.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
the maximum duration of PLM events was extended from 5
to 10 seconds and voltage amplitude criteria were used to
define a significant LM. Similar scoring criteria for PLMS
were published in the AASM scoring manual.47 The AASM
manual did not provide criteria for scoring PLMW. As
reviewed in Chapter 12, for LMs to be counted as part of a
PLM series (to be PLMs), they must be 0.5 to 10 seconds in
duration and have an amplitude greater than 8 V above the
resting baseline anterior tibial electromyogram (EMG) level.
The time of onset of successive LMs must be between 5 and
90 seconds. If two leg EMG bursts are separated by less than
5 seconds from onset to onset, they are considered a single
LM if they occur on the same or different legs. LMs must
occur in groups of four or more to be considered PLMs (part
of a PLM sequence). An LM is not scored as a PLM if it
occurs during a period starting 0.5 second before the start
of the apnea/hypopnea to 0.5 second after an apnea and
hypopnea. How to handle PLMs associated with RERAs was
not mentioned, but many clinicians would consider these as
associated with respiratory events.
PLMSI and PSG Findings
The PLMSI is the number of PLM events per hour of sleep.
The ICSD, first edition,48 listed the following grading of the
severity of PLMs: PLMSI < 5 normal, 524 mild, 2549
moderate, and 50/hr severe. However, these cutoffs are
entirely arbitrary and are not based on any outcome
data. Given the high prevalence of PLMS in asymptomatic
individuals, there is unlikely to be a value separating
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438 Chapter 23 The RLS, PLMS, and the PLMD
asymptomatic from symptomatic populations. The ICSD-2
chose a PLMSI greater than 15/hr in adults and greater
than 5/hr in children as part of the diagnostic criteria for
the PLMD.6 However, asymptomatic individuals can have
quite high PLMSI values.
PLMs occur most commonly in stage N1 and N2 but can
also occur in stage N3 or, less commonly, during stage R
sleep.49,50 The PLMSI is often higher during the first part of
the night. Culpepper and colleagues50 described two patterns
of PLMS. In one pattern, PLMS was much more common in
the first part of the night. In the second pattern, PLMS was
more evenly distributed across the night. The interval
between individual PLMs increases from stage N1 to stage
N3. PLMs are less likely to cause arousal from stage N3 sleep.
Frequent PLMs have been described during REM sleep in
patients with spinal cord injury51 and the RBD.52,53 The
AASM scoring manual did not define criteria for PLMW, but
others have used criteria similar to those used for PLMS54
(except that patients are awake). In PLMW, the periodicity
is less regular and shorter than typical of PLMS. It was found
that PLMW events tend to be longer (510 sec in duration)
compared with typical PLMS events.
PLMS and Arousals
An individual PLM and an arousal are considered to be
associated with each other when there is 0.5 second or less
from the end of one event to the onset of the other event
regardless of which is first.47 Overlapping events are consid-
ered to be associated. The PLMS arousal index is the number
of PLMS arousals per hour of sleep. There are no widely
accepted normal values for the PLMS arousal index. The
ICSD-148 listed a PLMS arousal index of 25/hr or greater as
severe. One study looking at the association of PLMs and
arousals found that 49% of electroencephalogram (EEG)
arousals occurred before PLMs, 30.6% simultaneously, and
23.2% occurred just after the LMs.55 PLMs can often be asso-
ciated with K complexes or delta bursts that do not meet
criteria for cortical arousal. Of note, autonomic changes
(increase in heart rate, increase in blood pressure, change in
pulse transit time) can occur in association with the PLMs
with and without cortical arousals56,57 and these auto-
nomic arousals are more common than cortical arousals.
Figure 233 shows the change in heart rate before and after
PLM events with and without cortical arousal. Of note, some
have hypothesized that PLMs and arousals are both second-
ary to a periodic central activation leading to both arousals
and PLMS.58,59 In one study of RLS patients, treatment with
L-dopa (LD) did not change the frequency of K-alpha com-
plexes, although the PLMSI decreased.58
Differential Diagnosis of PLMS
The differential of other periodic movements includes hyp-
nogogic foot tremor (HFT), alternating leg movement activi-
ties (ALMAs), excessive fragmentary myoclonus, and
rhythmic movement disorder.6,47 The reader is referred to
0.20
0.15 Onset of PLMS
R-R interval in seconds
0.10
0.05
0.00
0.05
0.10
0.15 With arousal
Without arousal
0.20
B1 B2 B3 B4 B5 A1 A2 A3 A4 A5 A6 A7 A8 A9 A10
Heart beats before (B1..B2..) and after (A1..A2..) PLM
FIGURE 233 Change in heart rate after periodic limb movements in sleep (PLMS).
The heart rate increased (R-R interval decreased) whether or not the PLM is associated
with a cortical arousal. The increase in heart rate is higher for a few beats after the
periodic leg movement (PLM) if an arousal is present. From Sforza E, Nicolas A,
Lavigne G, et al: EEG and cardiac activation during periodic leg movements in sleep.
Neurology 1999;52:786792.
Chapter 12 on movement monitoring for more details on
these entities.
Clinical Significance of the PLMSI and PLMS
Arousal Index
The clinical significance of PLMS and the utility of monitor-
ing LMs have been the subject of controversy59,60 and Pro-Con
debates.61,62 The utility of counting PLMS arousals has also
been questioned because the index does not appear to cor-
relate with subjective measures of disturbed sleep, daytime
sleepiness, or the sense of nonrestorative sleep.60 Clearly,
PLMs are very common in asymptomatic patient popula-
tions. For example, a PLMSI greater than 5/hr is seen in 30%
to 86% of adults aged 60 or older. Claman and associates9
studied 455 older community-dwelling women and found
that 66% had a PLMSI greater than 5/hr and 52% greater
than 15/hr. The associations between the PLMSI and the
PLMS arousal index with measures of sleep quality were
determined. The associations were adjusted for age, body
mass index (BMI), apnea-hypopnea index, and antidepres-
sant medication use. An increased PLMSI was associated
with a statistically significant higher total arousal index (but
the difference was very small) but not impairment of other
indices of sleep quality. A higher PLMS arousal index was
associated with lower total sleep time, less stage N3, and a
higher total arousal index. However, neither a higher PLMSI
nor a higher PLMS arousal index was associated with worse
subjective daytime sleepiness by Epworth Sleepiness Scale.
Carrier and coworkers63 found a PLMSI of greater than 10/
hr in 43/70 healthy middle-aged subjects without sleep com-
plaints. Sleep quality was not worse in those with a higher
PLMSI. The Pittsburgh Sleep Quality Index was slightly
worse in men with higher PLMSI. The difference was statisti-
cally significant but not clinically significant. It remains to
be determined whether determination of the PLMS arousal
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TABLE 236
Syndromes in which Periodic Limb Movements in
Sleep Are Common
DISORDER PREVALENCE OF PLMS
RLS 8090% with PLMSI > 5/hr
Narcolepsy 4565%5,59
REM sleep PLMS > 4/hr 70%52,53
behavior Unlike most other disorders, PLMs
disorder commonly continue during stage R
OSA 24%65
OSA = obstructive sleep apnea; PLMs = periodic limb movements; PLMS =
periodic limb movements in sleep; PLMSI = periodic limb movement in sleep
index; REM = rapid eye movement; RLS = restless legs syndrome.
index really adds anything of clinical significance to other
measures of sleep quality.
PLMS and Other Disorders
PLMS is common in a number of disorders other than RLS
(Table 236) including narcolepsy, the RBD, neuropathies of
diverse etiology, and OSA.5,52,53,6466 An increase in PLMSI
(compared to a diagnostic study) was noted during a con-
tinuous positive airway pressure (CPAP) titration and a
repeat study on CPAP (2 weeks to 7 months later).64 Chervin
and colleagues65 evaluated 1124 patients with suspected or
confirmed OSA and found that a higher PLMS arousal index
was associated with decreased objective sleepiness by mul-
tiple sleep latency test (MSLT). In this study, 24% of the OSA
patients had a PLMSI greater than 5/hr. In most patients
diagnosed with OSA on a sleep study, the incidental
finding of PLMS is usually of no or limited clinical signifi-
cance. It should prompt the clinician to check for symp-
toms of the RLS. PLMS can be associated with respiratory
eventrelated arousals (RERAs), and indeed, patients once
diagnosed with PLMD on the basis of PSG using thermal
airflow sensors can now be noted to have LMs associated
with RERAs66 due to more sensitive detection of subtle respi-
ratory events using nasal pressure monitoring of airflow. As
noted previously, LMs associated with apneas and hypop-
neas are not considered PLMs. Baran and associates67 found
PLMs tended to increase during the CPAP titration in severe
OSA patients but to decrease in milder OSA patients. They
hypothesized that CPAP unmasked PLMs in some severe
patients, but in the milder patients, prevented RERAs and,
therefore, decreased PLMs.
PERIODIC LIMB MOVEMENT DISORDER
In this disorder, PLMs, as described previously, result in
clinical sleep disturbance (sleep maintenance insomnia,
daytime sleepiness, or fatigue). The clinical symptoms are
not better explained by another primary sleep disorder. Thus,
the diagnosis depends on PSG to demonstrate PLMS and
exclusion of other causes of the symptoms by a clinical
Chapter 23 The RLS, PLMS, and the PLMD 439
BOX 2310
Periodic Limb Movement Disorder Diagnostic
Criteria (ICSD-2)*
A. PLMS presentLMs meet criteria to be PLMs
i. 0.510 sec in duration.
ii. Amplitude > 8 V above baseline.
iii. In a sequence of four or more movements.
iv. Onset of consecutive LMs >5 and <90 sec.
B. PLMS index >15/hr in adults, >5/hr in children.
C. There is a clinical sleep disturbance or complaint of
daytime fatigue.
D. The PLMS and clinical sleep disturbance are not better
explained by another current sleep disorder, medical or
neurologic, or psychiatric disorder.
Notes:
1. A diagnosis of RLS excludes PLMD.
2. If PLMs are present without sleep complaint, they can simply be noted as
a PSG finding.
3. If only the bed partners sleep is disturbed, this is not sufficient to make a
diagnosis of PLMD.
*Updated according to the AASM scoring manual.
LMs = limb movements; PLMs = periodic limb movements; PLMS = periodic
limb movements in sleep.
history and PSG (Box 2310). Recall that a diagnosis of RLS
excludes a diagnosis of PLMD. ICSD-1 stated The patient
has a complaint of insomnia or excessive sleepiness. The
patient occasionally will be asymptomatic, and the move-
ments are noticed by an observer. In ICSD-2,6 a complaint
of sleep disturbance by the patient is required for a diagnosis
of PLMD.
Prevalence and Manifestations of PLMD
Although PLMS is common, PLMD is thought to be rare.
The exact prevalence of the PLMD is unknown. Patients
rarely are aware that they have PLMS until informed by their
bed partner. The disturbance of the bed partners sleep by
PLMS is thought to be more common than PLMD. Some of
the patients previously thought to have PLMD on the basis
of sleep studies that monitored airflow with a thermal device
rather than nasal pressure may have actually had RERA or
hypopnea-associated PLMS. In these patients, the symptoms
of daytime sleepiness may have been due to mild OSA rather
than PLMD.66 Other patients with PLMD may have had
somewhat atypical symptoms of RLS without prominent
sensations. The finding of PLMS in children can be espe-
cially helpful because RLS symptoms are often difficult to
elicit. It has also been proposed that in children, PLMD
(PLMS with sleep disturbance) may precede the develop-
ment of symptoms of RLS.41
PSG and Objective Findings
The PLMSI in asymptomatic patients and patients with
PLMD overlap. The ICSD-2 criteria for PLMS include the
requirement of a PLMSI of 15/hr or greater in adults and
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440 Chapter 23 The RLS, PLMS, and the PLMD
5/hr or greater in children (see Box 2310). However, many
asymptomatic individuals have a PLMSI greater than 15/hr.
Mendelson60 evaluated a group of 67 patients felt to have the
PLMD. The patients had both a PSG and MSLT. The overall
sleep latency was around 10 minutes (near normal). There
was no significant correlation between the PLM arousal
index and the sleep latency on a MSLT or a measure of sub-
jective sleepiness.
TREATMENT OF RLS AND PLMD
Nonpharmacologic treatments of RLS may be appropriate in
mild or intermittent cases of RLS. Iron supplementation may
improve RLS symptoms if iron stores are low. A number of
medications (Table 237) can be used to treat RLS.6876 The
major medication groups include the dopaminergic medica-
tions (the dopamine precursor LD and dopamine agonists
[DAs]), opiates, anticonvulsant medications, and seda-
tive-hypnotic medications (usually benzodiazepine recep-
tor agonists [BZRAs]). Similar medications have been used
to treat the PLMD with the exception that opiates have not
been well studied for this indication. Of note, two DAs, rop-
inirole and pramipexole, are the only two medications that
are U.S. Food and Drug Administration (FDA) approved for
RLS treatment.
Nonpharmacologic Treatments
In mild and intermittent RLS, nonpharmacologic treatments
may be useful. These include stretching, heating or cooling
of the extremities (warm bath), and a trial of avoidance of
alcohol and caffeine. Antidepressant treatment can some-
times be associated with initiation or worsening of RLS.
However, if antidepressant treatment is deemed necessary,
RLS can be treated as if primary RLS was present. Studies
have suggested that bupropion either improves18 or does not
worsen PLMS,19 so use of this medication could be consid-
ered. However, concerns about RLS should not limit effec-
tive treatment of depression. Iron deficiency can cause or
worsen RLS. A ferritin level is recommended in RLS patients
because this disorder may be the only indication that low
iron stores are present. Most clinicians recommend that a
ferritin level above 45 to 50 g/mL be achieved in RLS
patients.17,70 Patients should also be evaluated for occult gas-
trointestinal blood loss if clinically indicated. Typical iron
supplementation is ferrous sulfate 325 mg tid with the addi-
tion of 100 to 200 mg of ascorbic acid with each dose (to
improve absorption). Iron absorption is better when ingested
with an empty stomach. However, some patients must take
iron with food to avoid severe gastrointestinal upset. Moni-
toring of ferritin levels is recommended to ensure adequate
replenishment of iron stores and to avoid inducing iron
overload. When ferritin levels exceed the goal, iron supple-
mentation can be stopped. It is important to note that iron
supplementation alone does not always improve RLS.
However, many patients will have better results with treat-
ment with standard RLS medications.
Dopaminergic Medications
LD is a precursor that is converted to dopamine by dopa
decarboxylase (DDC). Carbidopa (CD) does not penetrate
the blood-brain barrier but acts as an inhibitor of DDC
outside the central nervous system. Therefore, there is less
peripheral conversion of LD to dopamine. This results in
fewer side effects and an increased amount of LD reaching
the brain. LD/CD is very effective in RLS and has a quick
onset of action.6871 There are two problems with use of LD/
CD in treating RLS. First, the drug has a short duration of
action and there may be a rebound in symptoms in the early
morning hours. The patient can take another dose at that
time. There are longer-acting forms of LD/CD but they have
a slower onset of action. The second problem is that contin-
ued use of LD/CD, especially at high doses (LD > 200 mg/
day), commonly results in augmentation (a change in the
effectiveness of dopaminergic medications, discussed later).
In some studies, up to 80% of patients taking LD/CD for RLS
develop augmentation.72
The ergotamine-related DA pergolide is effective but
rarely used for RLS treatment due to the severe associated
nausea and the rare potential for retroperitoneal fibro-
sis.68,69,72 The nonergotamine DAs pramipexole and ropini-
role are considered the treatments of choice for moderate to
severe RLS.69,70 Randomized, controlled studies have docu-
mented the efficacy of these medications for treating RLS
and PLMD.7377 They have a sufficiently long duration of
action such that rebound usually does not occur. Augmenta-
tion, discussed in detail later, can occur in up to 30% of
patients but is usually mild and can be controlled by taking
a portion of the dose at an earlier time (split dose).70,78 Both
augmentation and side effects from the DAs can be mini-
mized by starting at a low dose (0.125 for pramipexole and
0.25 mg for ropiniriole) with a slow upward titration every
3 to 5 days as needed. It is important to note that both drugs
have a long time of onset of 1 to 3 hours and, ideally, should
be taken at least 2 hours before symptoms are expected. If
patients have symptoms in the morning, one can try treat-
ment with twice or three times a day dosing. Of note, some
patients will respond better to pramipexole than to ropini-
role and vice versa. Switching DAs is also an intervention
that can be tried if augmentation develops.
Few studies have been published concerning treatment of
PLMD and RLS in children. No medication is FDA approved
for treatment of PLMD or RLS in children. However, it
appears that dopaminergic therapy is effective treatment for
PLMD or RLS in children.4143
All dopaminergic medications share similar side effects
(Box 2311). Nausea is the most common side effect, but
headache, light-headedness, somnolence, and insomnia can
occur. Less frequent side effects include peripheral edema
and sleep attacks. The dopamine dysregulation syndrome
is a dysfunction of the rewards system in subjects taking
dopamine treatment. The most common symptom is craving
for dopaminergic medication sometimes associated with
taking extra doses even in the absence of symptoms that
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 Chapter 23 The RLS, PLMS, and the PLMD 441

TABLE 237
Medications Used to Treat the Restless Leg Syndrome
DOSE USUAL HALF-LIFE (HR)/
FORMS INITIAL EFFECTIVE MAX DOSE TIME TO ONSET OF ELIMINATION
(MG) DOSE (MG) DOSE (MG) (24 HR) ACTION (H, R)
DOPAMINE PRECURSORS
CD/LD 25/100 1 1 tablet
2 100200 of 200 LD hs 30 min 1.53 H
(Sinemet) of 25/100 LD
CD/LD CR 25/100 1 1 tablet
2 100200 of 200 LD hs 120 min 68 H
(Sinemet CR) 50/200 of 25/100 LD
DOPAMINE AGONISTS
Pramipexole 0.125 0.125 0.250.75 1.5 mg 120 min 812 R
(Mirapex) 0.25 23 hr max effect
Ropinirole 0.25 0.25 0.52.0 4.0 mg 60120 min 6H
(Requip) 0.5 2 or 3 divided 13 hr max effect
doses
OPIOIDS
Propoxyphene 100 100 100 100 mg q4h 1560 min, peak level 46 H, R
napsylate 32, 65 65 65 600/24 hr 22.5 hr
(Darvon) 65 mg q4h
Propoxyphene HCl 390/24 hr
HC/APAP (Lortab, 5, 7.5, 5 515 HC 2030 mg/day 1.3 hr peak level 34
Vicoden) 10/325 in 2 or 3 (hydrocodone)
5, 7.5, divided doses
10/500
Oxycodone 5, 10, 15 5 515 530 q4h 1015 min, peak level 36 H, R
3060 min
Methadone 5, 10 2.55 515 15 3060 min 859 H
Tramadol 50 50 50100 50100 q4h 1 hr, peak level 23 hr 67 H
400 mg/24 hr
BENZODIAZEPINE RECEPTOR AGONISTS
Clonazepam 0.5 0.25 0.251.0 2 mg 60120 min peak 1939 H
(Klonopin) level
Temazepam 15, 30 30 (15 1530 30 mg 4560 min, peak level 89 H
(Restoril) elderly) 90120 min
Zolpidem 5, 10 10 (5 elderly) 510 10 mg 30 min, peak level 2.53 H
Zolpidem-CR 6.25, 12.5 12.5 (6.25 6.2512.5 12.5 mg 90 min
(Ambien CR) elderly)
Eszopiclone 1, 2, 3 2 (1 elderly) 23 3 mg <30 min, peak level 6H
(Lunesta) 60 min
Zalpelon (Sonata) 5, 10, 20 10 1020 20 mg 1530 min, peak level 12 H
3090 min
ANTICONVULSANTS
Gabapentin 100, 300 300 6001800 2400 mg Peak level 24 hr 57 R
(Neurontin) 200300 Slow upward titration
after HD recommended
APAP = acetaminophen; CD = carbidopa; CR = controlled release; H = hepatic metabolism; HC = hydrocodone; HD = hemodialysis; LD = l-dopa; R = renal metabolism.

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442 Chapter 23 The RLS, PLMS, and the PLMD

BOX 2311 BOX 2312

Side Effects from Dopaminergic Medications Approaches to Augmentation
COMMON ACUTE EFFECTS 1. If on LD/CD, stop and change to a DA (avoid LD/CD in
daily RLS, avoid dose > 200 mg LD).
Nausea, less commonly vomiting
2. If on a DA and earlier symptom onset is the problem,
Light-headedness, rarely syncope
split the dose and give half of the dose earlier.
Headache
3. If patient is taking a DA, try changing to the other DA.
Somnolence
4. If patient is taking a DA and morning symptoms are a
Insomnia
problem, try an evening and morning dose of
LESS COMMON ADVERSE EFFECTS medication.
Peripheral edema 5. If very severe augmentation, stop the DA or LD/CD and
add high-potency opiate.
Sleep attacks
6. Avoid high doses of DAs, use combination therapy (add
Dopamine dysregulation syndrome
opiate, gabapentin, or BZRA).
Craving for dopaminergic medications including
7. Low iron stores may predispose to augmentation.
taking extra doses without clinical symptoms
BZRA = benzodiazepine receptor agonist; CD = carbidopa; DA = dopamine
Impulse control disorders
agonist; LD = L-dopa; RLS = restless legs syndrome.
Hypersexuality
Pathologic gambling
Excessive shopping Augmentation
SUBACUTE TO LATE-ONSET ADVERSE EFFECTS Augmentation is defined as a change in the efficacy of RLS
Augmentation treatment with dopaminergic medications70,78 (see Box 23
Advance in time of onset of symptoms 11). It is characterized by one or more of the following: (1)
Greater severity of symptoms when present earlier symptom onset, (2) greater severity of symptoms at
Reduced latency to onset of symptoms at rest the same dose, (3) reduced latency to onset of symptoms
Spread of symptoms to involve new body parts with rest, and (4) spread of symptoms to involve new body
parts (arms as well as legs). The greater severity of symptoms
ADVERSE EFFECTS PRIMARILY NOTED IN PARKINSONS is often noted even though medication dose has been
DISEASE
increased. Patients with severe augmentation are usually on
Dyskinesias LD/CD or a very high dose of a DA. As noted previously,
Hallucinations augmentation is common on daily LD/CD (80%) but can
Psychosis occur in patients taking a DA (30%)although it is usually
SIDE EFFECTS ASSOCIATED WITH ERGOTAMINE milder. When using a DA, it is imperative to be certain the
DOPAMINE AGONISTS patient is taking the DA early enough before increasing the
dose. Using the lowest effective dose of DA is prudent to
Severe nausea
minimize augmentation.
Fibrotic syndromes
Approaches to augmentation are listed in Box 2312. Low
Retroperitoneal fibrosis
iron stores appear to increase the frequency or severity of
Pleural-pulmonary fibrosis
augmentation so this problem should be treated if dopami-
Fibrotic cardiomyopathy
nergic medications are being used.80 If the patient is on LD/
Valvular disease
CD, the first approach would be to change to a DA. If the
Adapted from Hening WA, Buchfuhrer MJ, Lee HB: Clinical Management of
Restless Legs Syndrome. West Islip, NY: Professional Communications, 2008.
patient is on a DA and symptoms occur earlier in the evening,
the medication dose could be split or another dose added
earlier (e.g., pramipexole 0.125 mg at 6 PM and 9 PM). If the
problem is morning symptoms, a morning dose could be
indicate the need for additional medication. It can also be added (bid to tid dosing). Sometimes a midday dose is not
associated with defects in impulse control (compulsive gam- needed due to the RLS protected time period in the middle
bling, hypersexuality, or compulsive shopping). While the of the day. If RLS symptoms become more intense on the
dopamine dysregulation appears to be more common in Par- current dose of DA, approaches include an increase in dose
kinsons disease than in RLS, the problem is increasingly (unless already on a high dose) or a switch to the other DA.
reported as complication of DA treatment of RLS.79 When Sometimes patients respond better to one DA than to the
the DAs are used to treat Parkinsons disease in much other. Many physicians would rather add another class of
higher doses than those used to treat RLS, they can be associ- medication (an opiate or gabapentin) rather than increase
ated with dyskinesias, hallucinations, or psychosis. The the DA dose above a moderate level. If augmentation is
ergotamine-derived DAs (pergolide) are rarely used today. severe or the current DA dose is high, the best approach is
They are associated with severe nausea and, rarely, fibrotic probably stopping the DA (although severe exacerbation of
syndromes. RLS can occur) and adding a high-potency opiate with or
DaneshGroup.com

without another class of medication. Clearly, the best
approach is to not use LD/CD for daily RLS, use the lowest
dose possible of the DA with slow upward titration, and cor-
rection of low iron stores (goal ferritin > 4550 g/L).
Opioids/Opiates
Opiates and opioid receptor agonists (tramadol) can be
effective treatment for RLS.70,81,82 They are fairly rapidly
acting and can be used either singly or in combination with
other medication groups such as DAs. Milder RLS may
respond to low-potency opiates (propoxyphene, codeine) or
opioid agonists (tramadol). Moderate to severe RLS may
respond to high-potency opiates (hydrocodone, oxycodone,
methadone). Hydrocodone is available in the United States
in combination with acetaminophen (APAP). One must be
cautious not to prescribe an excessive dose of APAP. For
example, it is preferable to use hydrocodone/APAP 10/325
rather than 2 tablets of 5/325 mg. A maximum of 2 g of
APAP/day can be used, although lower doses can be harmful
if liver disease is present. Side effects of opiates include
nausea and constipation. These medications should not be
used with alcohol and should be used with caution in patients
with OSA. Due to the potential of abuse and dependence,
opiates are not the drugs of choice for daily RLS. However,
studies and clinical experience suggest that dependence is
not a problem if patients do not have a history of opiate
dependence and take medication only at night. Typical doses
of opiates/opioid agonists to treat RLS include tramadol 50
to 100 mg, propoxyphene napsylate 100 mg, hydrocodone 5
to 15 mg, oxycodone 5 to 15 mg, and methadone 5 to 15 mg
(see Table 237).70
Anticonvulsant Medications
Although a number of these medications have been used
(including carbamazepine, valproic acid, and gabapentin),
gabapentin is preferred because of its better safety profile.
Some consider gabapentin the drug of choice for patients
with RLS associated with pain.70 The efficacy of gabapentin
has been demonstrated by uncontrolled83 and controlled84
trials in patients with RLS. One of these studies also reported
a decrease in the PLMSI compared with placebo.84 Patients
reporting the symptoms of pain received the most benefit
from gabapentin. The usual starting dose of gabapentin is
300 mg administered at night 1 2 to 1 hour before symptoms.
The average effective dose is quite high (9001500 mg) (Fig.
234). Side effects include sedation, fatigue, ataxia, nausea,
and peripheral edema. Serious reactions include leukopenia,
thrombocytopenia, and depression. A slow upward titration
has been used in studies of gabapentin with an increase of
300 to 600 mg every 1 to 2 weeks. This may improve toler-
ance to relatively high doses of gabapentin. A controlled
cross-over study demonstrated that gabapentin was effective
treatment of RLS in renal failure patients on hemodialysis.85
In this study, a dose of 200 to 300 mg was given after each
dialysis session. Gabapentin is cleared by the kidney so a
Chapter 23 The RLS, PLMS, and the PLMD 443
22
(*) ** **
RLS - rating scale mean total score
20
18
PLB
16
14
GBP
12
10
8
2500
Dose of GBP (mg)
2000
1500
1000
500
0
BL W.2 W.4 W.6
FIGURE 234 Change in restless legs syndrome (RLS) symptoms (RLS rating scale, see
Box 238) on gabapentin (GBP) and placebo (PLB) during dose escalation. *P = NS;
** P < .05 GBP vs. PLB. Note that fairly high doses of GBP were needed to be effective.
BL = baseline; W.2, W.4, W.6 after 2, 4, and 6 weeks of treatment. From Garcia-
Borreguero D, Larrosa O, de la Llave Y, et al: Treatment of restless legs syndrome with
gabapentin. Neurology 2002;59:15731579.
reduced dose is needed in patients with renal insuffi-
ciency. One problem with gabapentin is that there is large
interpatient variability in absorption and plasma levels due
to saturable absorption in the upper intestine. The prodrug
gabapentin enacarbil (GEn, XP13512) is rapidly absorbed
throughout the gastrointestinal tract and, once absorbed, is
converted to gabapentin. This drug delays the time to peak
gabapentin plasma levels and provides dose-proportional
exposure. A placebo-controlled study demonstrated efficacy
of GEn for RLS treatment.86 This medication may be a treat-
ment alternative in the future. A recent double-blind, pla-
cebo-controlled study found that pregabalin (Lyrica) in a
mean dose of 333 mg was an effective treatment for RLS.87
Treatment was started at 150 mg and increased as needed.
Pregabalin (like gabapentin) is a ligand that binds to the 2
(alpha2delta) subunit of the voltage-dependent calcium
channel in the central nervous system. Pregabalin was devel-
oped as an anticonvulsant but is approved for treatment of
neuropathic pain and fibromyalgia. Side effects include diz-
ziness and drowsiness, blurred vision, and ataxia. It is more
expensive than gabapentin but could be considered if a
patient does not tolerate or improve with a DA and does not
tolerate gabapentin.
Sedative Hypnotics
The BZRAs including both benzodiazepines (triazolam,
temazepam, clonazepam) and nonbenzodiazepines
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444 Chapter 23 The RLS, PLMS, and the PLMD

TABLE 238
Benzodiazepine Receptor Agonists and Periodic Limb Movement in Sleep/Periodic Limb Movement Disorder
MEDICATION/ DECREASED IMPROVED
STUDY STUDY DESIGN DISORDER PLMSI SLEEP IMPROVED SYMPTOMS
Clonazepam and Case series PLMS No Sleep efficiency improved Improved
temazepam subjective sleep
Mitler, 198688 quality but not
alertness
Clonazepam Placebo-controlled PLMS Yes Sleep latency decreased N/A
Peled, 198789 Sleep efficiency improved
Triazolam Double-blind, PLMS with sleep No Sleep efficiency increased Objective daytime
Bonnet, 199090 placebo-controlled fragmentation Total sleep time increased alertness
cross-over improved
Triazolam Cross-over, placebo- PLMS No Decreased PLM arousal Less daytime
Doghramji, 199191 controlled index sleepiness MSLT
Clonazepam Placebo-controlled, PLMD and RLS No Yes Improved
Saletu, 200192 single-blind with subjective sleep
cross-over with quality
clonazepam given
first
MSLT = multiple sleep latency test; N/A = not applicable; PLM = periodic limb movement; PLMD = periodic limb movement disorder; PLMS = periodic limb
movement in sleep; PLMSI = periodic limb movement in sleep index; RLS = restless leg syndrome.

(zolpidem, zaleplon, eszopiclone) can be used for treatment
of RLS or PLMD.70,8892 Clonazepam, a potent and long-
acting BZRA, has been the most studied88,89,92 (Table 238).
The BZRAs work mainly by reducing the sleep latency,
increasing sleep efficiency, and reducing the arousals due to
PLMS. Most studies have NOT found a decrease in the
PLMSI. Unfortunately, clonazepam can cause profound
morning grogginess due to its long half-life. The BZRAs with
a short duration of action (triazolam,90,91 zaleplon, or zolpi-
dem) or an intermediate duration of action (zolpidem-CR,
eszopiclone, temazepam) are likely to be as effective and
better tolerated. In patients with early morning awakening,
a change from the shorter-acting to the medium-duration
medications may be helpful. This class of medications should
be used with caution in patients with OSA or severe lung
disease. Side effects include hallucinations, sleep-related
eating disorder, confusion, falls, morning grogginess, and
unpleasant taste (eszopiclone).
RLS Treatment Algorithm
In choosing treatment, it is useful to classify the patient using
the approach of Silber and coworkers70 into the following
groups: (1) mild/intermittent RLS symptoms, (2) daily RLS
symptoms, and (3) refractory RLS symptoms (Table 239).
The mild/intermittent group may be treated with conserva-
tive measures such as avoiding precipitating medications
(sedating antihistamines) and substances (alcohol, caffeine),
warm baths, and iron supplementation if there are low iron
stores. If a RLS medication is used, it should be rapidly acting
because the patient can often not predict that symptoms will
occur. LD/CD in the short-acting form is active within 1 2
hour and, therefore, is a good choice for treatment with
intermittent RLS (that may not be predictable). A DA will be
effective, although the time to onset is delayed for 1 to 3
hours. Ropinirole may have a more rapid effect than prami-
pexole. Other choices are low-potency opiates such as pro-
poxyphene or codeine. Sedative-hypnotics may also be
effective.
Daily RLS
Daily RLS of moderate severity requires a different approach
from milder disease. Although LD/CD may be effective, it is
associated with augmentation in 80% of the cases. In addi-
tion, due to the short duration of action, patients may have
rebound (return of symptoms in the middle of the night or
morning). The options are taking an additional short-acting
LD/CD in the middle of the night or using a continuous-
release LD/CD preparation. The longer-acting preparation
has a slow onset. One of the nonergotamine DAs (ropini-
role or pramipexole) is considered the treatment of choice
for daily/moderate to severe RLS.70
The initial dose should be low (0.125 pramipexole 0.25
ropinirole) and given 2 hours before symptom onset. The
dose can be slowly increased every 3 to 5 days. The usual
effective dose ranges are 0.25 to 0.75 mg for pramipexole and
0.5 to 1.5 mg for ropinirole (higher doses have been used by
some clinicians). If a given DA is not effective, the other
should be tried because some patients respond better to
either pramipexole or ropinirole. If the clinical response is
inadequate or side effects prevent the use of the DA, a low- to
moderate-potency opiate, gabapentin, or a sedative-hypnotic
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 Chapter 23 The RLS, PLMS, and the PLMD 445

TABLE 239
Treatment Algorithm for Restless Leg Syndrome
Mild/intermittent RLS Nonpharmacologic
Pharmacologic
Daily RLS First choice
Second choice
Third choice (unless pain
or history of addiction)
Refractory RLS If DA is initially effective
but augmentation
RLS treated with DA then develops.
1. Inadequate initial response Moderate to severe
2. Response inadequate with augmentation or DA
time not tolerated
3. Intolerable side effects
4. Augmentation Moderate to severe
augmentation or DA
not tolerated
Pain prominent
Addiction concerns
Inadequate initial
response
DA only partially effective
at moderate dose or
highest tolerated dose.
APAP = acetaminophen; BZRA = benzodiazepine receptor agonist; DA = dopamine agonist; RLS = restless legs syndrome.
Abstain from caffeine, nicotine, alcohol.
Iron replacement.
Discontinue drugs (find alternate) that may worsen or cause RLS.
Alerting activities.
Levodopa/carbidoparapid onset.
DAslow onset (2 hr).
Low-potency opiates/opioid agonist (propoxyphene, tramadol).
Sedative-hypnotic BZRA.
DA
Opiateslow to high potency
Gabapentin
Sedative-hypnotic
Split DA dose
Change to another DA
Change to high-potency
opiate
Change to gabapentin
Add BZRA, opioid, or
gabapentin to DA
Ropinirole or pramipexole
If side effects or not
effective, change to the
other DA.
If side effects on both DAs,
use second or third choice.
Low potency:
propoxyphene, tramadol.
High potency:
hydrocodone/APAP,
oxycodone, methadone.
Use DA if unsuccessful.
Gabapentin may be first
choice in patients with
painful sensations.
Use DA if unsuccessful.
Ropinirole (0.251.5 mg)
Pramipexole (0.1250.75 mg)
Oxycodone (515 mg),
methadone (510 mg).
Start gabapentin 300600 mg,
lower in elderly, or renal
failure.
May require 13001800 mg
Multiagent treatment may
avoid use of high doses of a
single agent.

should be tried. If side effects are noted at higher doses of
a DA, one might also combine a lower dose of DA with
another class of medications. If the RLS is associated with
pain, some physicians recommend starting with gabapentin
instead of a DA.
Refractory/Severe RLS
Refractory RLS is defined as (1) inadequate initial response
despite adequate dose (and timing of dose), (2) response has
become inadequate over time, (3) intolerable side effects
have occurred, or (4) augmentation is present. The approach
to augmentation has already been discussed. Treatment
approaches to refractory/severe RLS include (1) switch to
another DA, (2) add an opioid, gabapentin, or BZRA, (3)
change from a DA to gabapentin, or (4) change to a high-
potency opioid. Because of the difficulty in treating severe
augmentation, it is best to avoid very high doses of DAs if
possible.
DaneshGroup.com
446 Chapter 23 The RLS, PLMS, and the PLMD
CLINICAL REVIEW QUESTIONS
1. A 40-year-old woman has nightly restless legs symptoms
that delay her sleep onset. She was started on pramipexole
0.125 mg at bedtime and this was increased to 0.325 mg
without much benefit. What do you recommend?
A. Change to ropinirole.
B. Increase pramipexole dose to 0.5 mg.
C. Add tramadol 50 mg.
D. Administer current dose of pramipexole earlier.
2. A 30-year-old woman has intermittent RLS on long car
trips. Although these episodes occur infrequently, they
are quite distressing. She has to stop and walk around
every 100 miles or the symptoms become intolerable. A
recent ferritin level was 100 g/L. What do you
recommend?
A. Pramipexole 0.125 mg before long car trips.
B. LD/CD 25/100 mg before long car trips.
C. Iron supplementation.
D. Gabapentin 100 mg before long car trips.
3. A 40-year-old man has developed severe RLS symptoms
nearly every night. He was started on LD/CD 100/25 mg
at bedtime with good initial response. When RLS
symptoms returned, the dose was increased to 200/25.
After 1 week on this dose, RLS symptoms were noted
in both the arms and the legs and the symptoms
started at 6 PM rather than 10 PM nightly. What do you
recommend?
A. Increase LD/CD to 300/75 mg.
B. Take an earlier dose of LD/CD.
C. Add oxycodone 5 mg nightly at bedtime.
D. Stop LD/CD and start ropinirole at 0.25 mg.
4. A 25-year-old woman with daily RLS symptoms was
started on pramipexole 0.125 mg and this was increased
to 0.75 mg over several weeks. The patient feels that her
RLS symptoms have improved but continue at a signifi-
cant level. Her ferritin level is 100 g/L. What do you
recommend?
A. Increase pramipexole to 1.0 mg.
B. Switch to ropinirole 0.5 mg.
C. Add oxycodone 510 mg.
D. Add gabapentin 100 mg.
5. A patient with diabetic neuropathy reports RLS symp-
toms that are quite painful and distressing. There is a
history of alcohol and valium dependence in the past.
What do you recommend for initial treatment?
A. Gabapentin 300 mg in the evening.
B. Ropinirole 0.25 mg in the evening.
C. Oxycodone 10 mg in the evening.
D. Clonazepam 0.25 mg at bedtime.
6. A 50-year-old woman is currently taking pramipexole
1.0 mg and zolpidem 10 mg for severe symptoms of RLS.
The symptoms were in fair control but are now present
much earlier than when she started treatment. Initially,
her symptoms began around 11 PM but now are noted as
early as 8 PM. What do you recommend?
A. Change to pramipexole 0.25 mg at 6 PM and 0.75 mg
at 9 PM.
B. Change from pramipexole to ropinirole.
C. Add oxycodone 5 mg.
D. Increase pramipexole dose.
7. A 50-year-old man with a history of snoring undergoes a
split-night sleep study. The diagnostic portion shows an
apnea-hypopnea index (AHI) of 50/hr. The CPAP titra-
tion finds that on CPAP of 10 cm H2O the AHI is 5/hr.
The PLMSI is 50/hr. The patient does not report symp-
toms of the RLS. The patients wife does report that he
kicks during sleep. What treatment do you recommend?
A. CPAP of 10 cm H2O and pramipexole.
B. CPAP of 10 cm H2O.
C. CPAP of 10 cm H2O and gabapentin.
D. CPAP and iron supplementation.
8. Which of the following disorders has been associated
with PLMS?
A. Narcolepsy.
B. RBD
C. OSA.
D. All of the above.
9. A 12-year-old boy has difficulty staying awake. He does
NOT report an urge to move the legs or unusual sensa-
tions. His parents have noted that the patient is a restless
sleeper, moves around in bed a lot, and sometimes snores.
The patient is fidgety in school and has problems con-
centrating. A PSG is ordered to rule out OSA. The sleep
study shows mild snoring, no apneas and hypopneas, and
no elevation in end-tidal partial pressure of CO2. The
PLMS index is 15/hr. What is your diagnosis?
A. RLS.
B. Snoring.
C. PLMD.
D. ADHD.
Answers
1. D. Ropinirole and pramipexole should be given 2 hours
before bedtime (or evening symptom onset). These medi-
cations have a slow onset of action. A higher dose of
pramipexole could be needed but the first intervention is
to have the patient take the medication earlier.
2. B. LD/CD is a useful medication for intermittent RLS
owing to the rapid onset of action. However, the duration
DaneshGroup.com

of action is short and augmentation frequently occurs
with daily use. Iron supplementation is recommended for
RLS patients with a ferritin level <4550 g/L.
3. D. This patient has significant augmentation on LD/CD.
This medication should be stopped and the patient
changed to a DA. Low iron stores should also be ruled
out by a ferritin level in this patient.
4. C. The patient is on a fairly high dose of pramipexole for
RLS treatment. She is tolerating the medication but sig-
nificant symptoms persist. It is possible that an increase
to 1 mg pramipexole will be effective but could increase
the risk of augmentation. However, some would argue
that A is also a correct answer. A change to a different DA
is another option. The equivalent dose of ropinirole is
around twice that of pramipexole. Ropinirole at a dose of
0.5 mg is NOT an equivalent dose compared with prami-
pexole of 0.75 mg. To avoid the risk of augmentation,
most clinicians avoid high doses of DAs. The addition of
oxycodone 5 to 10 mg is probably the most effective
option. The addition of a BZRA or gabapentin could be
tried in this situation. However, 100 mg of gabapentin is
unlikely to be effective.
5. A. The patient has a history of drug dependence; there-
fore, benzodiazepines and narcotics should be avoided.
Gabapentin is recommended when RLS symptoms are
painful. Ropinirole may be effective in this setting but
may not improve symptoms of pain. Of note, gabapentin
at a dose of 300 mg may not be effective. A dose of 900
to 1500 mg is often needed. Slow upward titration may
reduce side effects.
6. A. The earlier onset of symptoms is a form of augmenta-
tion. Because pramipexole was fairly effective and well
tolerated, the first intervention should be use of a split
dose with a portion of the medication given earlier in the
evening. If this is not effective, either B or C is a reason-
able intervention. The patient is already on a high dose of
pramipexole; therefore, a further increase in dose in the
setting of augmentation is probably not indicated.
7. B. The patient has no RLS symptoms. PLMS is frequently
associated with OSA and usually does not require treat-
ment. Treatment with CPAP of 10 cm H2O should be
started. If frequent LMs persist and are significantly
impairing sleep quality, treatment could then be consid-
ered. Iron supplementation should not be started without
demonstration of low iron stores.
8. D. PLMS have been associated with narcolepsy, the RBD,
and OSA.
9. C. PLMD. In pediatric patients, PLMD sometimes pre-
cedes symptoms of the RLS. A PLMSI of 15/hr might be
of no significance in an adult but for a child is signifi-
cantly elevated. There has been an association between
ADHD and RLS/PLMD.
Chapter 23 The RLS, PLMS, and the PLMD 447
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68. Hening WA, Allen RP, Earley CJ, et al: An update on the dopa-
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76. Allen R, Becker PM, Bogan R, et al: Ropinirole decreases peri-
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77. Saletu M, Anderer P, Saletu B, et al: Sleep laboratory studies in
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78. Winklemann JW, Johnson L: Augmentation and tolerance with
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79. Cornelius JR, Tippmann-Peikert M, Slocumb NL, et al: Impulse
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81. Walters AS, Wagner ML, Hening WA, et al: Successful treat-
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82. Kaplan PW, Allen RP, Bucholz DW, Walters JK: A double-blind,
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83. Happe S, Sauter C, Klosch G, et al: Gabapentin versus ropini-
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85. Thorp ML, Morris CD, Bagby SP: A crossover study of gabap-
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Hypersomnias of Central Origin
Chapter Points
N+C and NC are two disorders characterized by EDS
and symptoms related to the abnormal regulation of
wake and sleep. A short REM latency and intrusion of
REM sleep features into wake are characteristic of the
disorders.
Cataplexy is characterized by temporary muscle
weakness induced by emotional stimuli. The affected
individual is conscious and the duration of weakness is
usually seconds to minutes. Hearing or telling a joke
and laughter are the most common triggers.
Approximately 6070% of patients with narcolepsy
have cataplexy.
Cataplexy is the only symptom virtually specific for
narcolepsy. Cataplexy in the absence of narcolepsy
occurs only in patients with a few rare genetic
disorders. Patients with these disorders have
abnormal neurological function.
Approximately 9095% of patients with N+C have low
or absent Hcrt1 in the CSF and absent Hcrt-producing
neurons in the lateral hypothalamus.
Other manifestations of narcolepsy include sleep
paralysis, sleep-related hallucination, automatic
behavior, disturbed sleep, and the RBD.
The hallucinations of narcolepsy that occur at
nocturnal sleep onset are called hypnagogic
hallucinations and those on awakening are termed
hypnopompic hallucinations.
For N+C, the MSLT is confirmatory. The diagnosis of
NC depends on demonstration of sleep-onset REM
periods in the absence of other sleep disorders (such
as sleep apnea) that can cause a short REM latency.
The MSLT criteria for narcolepsy are a mean sleep
latency 8 min and two or more sleep-onset REM
periods.
IH with a long sleep time in contrast to IH without a long
sleep time is characterized by a typical sleep duration of
longer than 10 hours. The diagnosis depends on
exclusion of other disorders that could explain the EDS.
The MSLT criteria for IH are mean sleep latency <8
minutes and fewer than 2 sleep REM-onset periods.
Treatments for the EDS of narcolepsy include modafinil
(and armodafinil), stimulants (methylphenidate and
others), and sodium oxybate.
Chapter 24
Treatments for cataplexy include sodium oxybate (FDA
approved) and nonFDA-approved medications
including TCAs, SSRIs, and SNRIs. These medications
also decrease sleep paralysis and HHs.
Treatments for the EDS of IH include modafinil
(armodafinil) and stimulants.
The hypersomnias of central origin are those conditions in
which hypersomnia is due to dysfunction of the central
nervous system (CNS). The dysfunction is not due to sleep-
related breathing disorders (SRBDs), circadian rhythm sleep
disorders, or other causes of disturbed nocturnal sleep.
Although the nocturnal sleep in some of these disorders is
not normal, the daytime sleepiness is out of proportion to
the degree of sleep disturbance. The International Classifi-
cation of Sleep Disorders, 2nd edition (ICSD-2)1 lists a
number of disorders in the category Hypersomnias of
Central Origin (Box 241). This chapter discusses the dis-
orders with the emphasis on narcolepsy with and without
cataplexy.
NARCOLEPSY SYNDROMES
Narcolepsy is a chronic disorder characterized by excessive
daytime sleepiness (EDS) and symptoms related to the
abnormal regulation of wakefulness and sleep. It is charac-
terized by a short rapid eye movement (REM) latency and
intrusion of REM sleep features into the waking state.
Approximately 60% to 70% of all patients with narcolepsy
have cataplexy.14 Cataplexy consists of temporary muscle
weakness following emotional stimuli. Narcolepsy with cata-
plexy (N+C) and narcolepsy without cataplexy (NC) are
now classified as two distinct disorders but share many of
the same features14 (Table 241).
As the name implies, definitive cataplexy is present in
patients with N+C. Following the discovery of hypocretin
(Orexin) peptides in 1998,5,6 it was learned that the majority
of patients with N+C have low or undetectable levels of
hypocretin-1 (Hcrt1) in the cerebrospinal fluid (CSF).7
However, much more much remains to be determined about
the pathophysiology of narcolepsy. In the absence of cata-
plexy, a diagnosis of NC depends on demonstration of
sleep-onset REM (very short REM latency) and an absence
of other disorders to explain this finding.14
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451
452 Chapter 24 Hypersomnias of Central Origin

BOX 241
Hypersomnias of Central Origin
1. Narcolepsy with cataplexy
2. Narcolepsy without cataplexy
3. Narcolepsy due to medical condition
4. Narcolepsy unspecified
5. Idiopathic hypersomnia with long sleep time
6. Idiopathic hypersomnia without long sleep time
7. Recurrent hypersomnia
8. Behaviorally induced insufficient sleep
9. Hypersomnia due to medical condition
10. Hypersomnia due to drug or substance
11. Hypersomnia not due to substance or known
physiologic condition (including hypersomnia due to
mental disorder) (nonorganic hypersomnia [NOS])
12. Physiologic (organic) hypersomnia, unspecified
From American Academy of Sleep Medicine: International Classification of
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
History
The key symptoms of narcolepsy were described by West-
phal in 1877.8 The term narcolepsy, meaning to seize with
drowsiness, was coined by Gelinau.8 Aidie termed the loss
of muscle tone as cataplexy in the early 20th century.9 Yoss
and Daly10 described the classic tetrad of daytime sleepi-
ness, cataplexy, hypnagogic hallucinations, and sleep paraly-
sis (SP). In 1960, Vogel11 reported that sleep-onset REM
periods were associated with narcolepsy. Initially, the asso-
ciation of narcolepsy with the human leukocyte antigen
(HLA) DR2 antigen was described in Japanese patients.12
Later, the HLA DQB1*602 was found to be strongly associ-
ated with narcolepsy in white and African American popu-
lations.13 In 1998, two groups simultaneously reported the
existence of hypocretin (Orexin) peptides present in the
lateral and posterior hypothalamus.5,6 Cleavage of a single
precursor protein produces the peptides hypocretin-1
(Orexin A) and hypocretin-2 (Orexin B). In 2000, the asso-
ciation of narcolepsy with cataplexy and low or undetect-
able levels of CSF Hcrt1 was described.7

TABLE 241
Features of Narcolepsy
FEATURES OF SPECIFIC FOR
NARCOLEPSY COMMENTS NARCOLEPSY?
CLASSIC TETRAD SYMPTOMS
EDS Continuous daytime sleepiness, with exacerbations (sleep attacks). No
Usually first symptom.
Present in virtually 100% of narcolepsy patients.
Cataplexy Muscle weakness triggered by emotion. Yes
Most common triggers: hearing or telling a joke.
Onset usually occurs within a few years of the onset of sleepiness.
Duration: Seconds to minutes.
Consciousness preserved at least at beginning of episodes.
Present in 6070% of patients with narcolepsy.
Hypnagogic (at sleep onset) Vivid dreamlike images that occur at sleep-wake transitions. No
or hypnapompic (on Duration: Several minutes.
awakening) hallucinations Can be associated with SP.
Sleep paralysis A partial or complete paralysis of the skeletal muscles that occurs at sleep No
onset or sleep offset.
Can be associated with HPH > HH. The patient is awake but cant move.
Can be associated with dyspnea, although the diaphragm is not affected.
Duration: A few seconds to several minutes.
OTHER MANIFESTATIONS OF NARCOLEPSY
Disturbed nocturnal sleep Increased stage N1. No
Frequent awakenings.
2030% have short nocturnal REM latency (<15 min).
PLMS is common.
Automatic behavior Semipurposeful activity with amnesia. No
REM sleep behavior disorder Dream enactmentoften violent, REM without atonia. No
EDS = excessive daytime sleepiness; HH = hypnagogic hallucinations; HPH = hypnopompic hallucinations; PLMS = periodic limb movements during sleep;
REM = rapid eye movement; SP = sleep paralysis.
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 Chapter 24 Hypersomnias of Central Origin 453

Epidemiology HLA Typing

Narcolepsy is present in about 1/2000 persons. Approxi- N+C is strongly linked to specific HLAs. Approximately 90%
mately 60% to 70% of patients with narcolepsy have cata- to 95% of patients with N+C have the DQB1*0602 allele
plexy.14 Men and women are affected equally. The average regardless of race16 (see Table 242). However, this allele is
age of onset in most studies is between 20 and 30 years. present in about 12% of Japanese, 25% of whites, and 38% of
However, narcolepsy can begin at any age. Dauvilliers and African Americans without the syndrome. The percentage of
coworkers15 found two peaks in the age of onset with one patients with NC that are DQB1*0602 positive is lower
around age 15 and the other around 35 years of age. (4060%). In general, patients with narcolepsy who are
DQB1*602-positive have more severe symptoms.2
Genetics
Importance of Hcrt Neurons
Familial canine narcolepsy is transmitted as a single autoso-
mal recessive gene (canarc-1) with complete penetrance.16 Hcrt neurons located in the lateral or posterior hypothala-
This form of narcolepsy is due to an abnormal Hcrt2 recep- mus project widely in the CNS (Fig. 241A). They augment
tor. However, the human form of the narcolepsy is not a
simple genetic disease. Although the majority of cases of
human narcolepsy are sporadic, there have been numerous
reports of familial narcolepsy in the literature.16,17 Studies of
families of patients with narcolepsy revealed that the risk of Thalamus
a first-degree relative of a narcoleptic developing N+C is 1%
Orexin
to 2%, a 10 to 40 times higher risk than in the general popu- 
lation.16 However, studies of identical twins show a high

degree of discordance for N+C. That is, if one twin has nar- TMN 
colepsy, the other twin will have or develop narcolepsy only Raphe
about 25% to 31% of the time16 (Table 242). Thus, factors LC
other than genetics are important for the development of
human narcolepsy.

TABLE 242
Narcolepsy Facts
INCIDENCE OF NARCOLEPSY 1/2000
RISK FOR DEVELOPING Excitatory
Inhibitory
FAMILIAL RELATIONSHIP NARCOLEPSY
Identical twin has narcolepsy 2531% of other twin has
with cataplexy. narcolepsy.
First-degree relative has 12% (1040 higher risk). SLD Glu Glu
narcolepsy. SOM
Glu Interneurons
Motor neurons
HLA ANTIGEN PREVALENCE HLA DQB1*0602 POSITIVE
GABA/Gly
General population. 1238%. B
N+C. 90% (10% negative).
FIGURE 241 A, Orexin (Hypocretin) neurons in the hypothalamus project widely to
NC. 4060%. many brain areas responsible for maintenance of wakefulness including the
tuberomammillary nucleus (TMN), dorsal raphe, and locus coeruleus (LC). B, Possible
HYPOCRETIN CSF HYPOCRETIN-1
pathways mediating atonia of REM sleep. Neurons in the atonia areas of the pons, the
N+C Absent or low 90100%. sublateral dorsal nucleus (SLD), project directly to interneurons in the spinal cord that
Normal in up to 10%. inhibit motor neurons. An indirect pathway via the supraolivary medulla (SOM) is also
illustrated. Other pathways are also likely important. The atonia neurons are
NC 90% normal levels.
glutaminergic and the inhibitory spinal cord interneurons secrete glycine (Gly) and
510% reduced levels
gamma-aminobutyric acid (GABA). Glu = glucose. A, Adapted from Scammell TE: The
(most + for DQB1*0602).
neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003;53:154166.
CSF = cerebrospinal fluid; HLA = human leukocyte antigen; N+C = narcolepsy
B, Vetrivelan R, Fuller PM, Tong Q, Lu J: Medullary circuitry regulating rapid eye movement
with cataplexy; NC = narcolepsy without cataplexy.
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sleep and motor atonia. J Neurosci 2009;29:93619369.
454 Chapter 24 Hypersomnias of Central Origin
the activity of brain areas active during wakefulness (tuber-
omammillary nucleus [TMN]histamine, locus coeruleus
norepinephrine [NE], and dorsal rapheserotonin).1823
Their activity is believed to stabilize the sleep-wake system
to prevent abrupt transitions between sleep and wake-
fulness. Histaminergic neurons are located exclusively in
the TMN of the posterior hypothalamus and project to
various brain regions associated with regulation of sleep-
wake cycles. Activity of these histaminergic neurons is
believed to help promote wakefulness. Hcrt neurons project
to the TMN and stimulate the TMN neurons via Hcrt2
receptors.
Pathophysiology of Narcolepsy
N+C Group
As noted previously, canine N+C is usually secondary to a
defect in the receptor for Hcrt2. Human N+C is associated
with absent or very low CSF levels of Hcrt1 (90100% of
patients).15,2426 Brains of patients with N+C have reduced
staining for Hcrt in the hypothalamus.27,28 N+C is associated
with a loss of approximately 90% of Hcrt neurons. Melanin-
concentrating hormone neurons, which are intermixed with
Hcrt cells in the normal brain, were not reduced in number,
indicating that cell loss is relatively specific for Hcrt neurons.
It is believed that hypothalamic Hcrt cells are destroyed
before disease onset. Mutations in Hcrt genes do not appear
to be the cause of most human narcolepsy.29 Of note, up to
10% of patients with N+C have normal CSF Hcrt1 levels.25,26
Thus, other abnormalities of the Hcrt system or other mech-
anisms must be the cause of the syndrome in these patients.
The cause of the loss of Hcrt cells in patients with N+C is
unknown. Because of the association of narcolepsy with
HLA antigens, an autoimmune mechanism has been hypoth-
esized but has been difficult to document.30 Elevated anti-
streptococcal antibodies were found in one study of patients
with recent narcolepsy onset.31 Another study found that
narcolepsy is also associated with a polymorphism in the
T-cell receptor alpha gene.32 Recently, several studies have
found that some patients with narcolepsy have elevated levels
of antibodies against a protein known as Tribbles homolog 2
(TRIB2).3335 In one study, antibodies were found in about
25% of patients with N+C but in only 3.5% in patients with
NC or 4.5% in normal controls.35 The presence of TRIB2
antibodies was associated with a short duration since disease
onset (recent onset of narcolepsy). TRIB2 is produced in
Hcrt neurons, providing some of the firmest evidence yet for
an autoimmune cause of narcolepsy. However, whether the
Tribbles antibodies cause Hcrt damage, occur secondary to
damage of the Hcrt neurons, or are simply an associated
phenomenon secondary to another cause of Hcrt neuron
injury is unknown.36
Two investigations have documented low CSF histamine
in patients with narcolepsy (with and without cataplexy) and
idiopathic hypersomnia (IH).37,38 As noted previously, hista-
mine secretion is believed important for maintaining
wakefulness. It is not clear whether low CSF histamine is a
cause or an effect of EDS in these patients. Recall that Hcrt
neurons stimulate histaminergic neurons in the TMN.
However, CSF histamine was low even in patients without
Hcrt ligand deficiency (NC and IH). Therefore, other
defects beside Hcrt deficiency must be involved in producing
low CSF histamine levels.
NC Group
The pathophysiology of NC is not well understood. A
small percentage (510%) of NC patients have a reduced
CSF Hcrt (most are positive for HLA DQB1*0602). NC
patients negative for the HLA DQB1*0602 almost always
have normal CSF Hcrt1 levels.7,25,26 The etiology of NC
is currently unknown but may represent a dysfunction of
the Hcrt system without total loss of Hcrt-producing
cells. Thannickal and coworkers39 examined the brain of
one patient with NC and found a 33% reduction in hypo-
cretin cells (compared to normals) with maximal loss in
the posterior hypothalamus. Thus, partial loss of Hcrt
neurons and other alterations in the Hcrt system without a
reduction in CSF Hcrt could be the etiology of NC. As
noted previously, CSF histamine is low in NC patients.37,38
This may be a marker of hypersomnia, or reduced hista-
mine secretion could be part of the pathogenesis of the
disorder.
Mechanisms of Cataplexy
The mechanisms inducing cataplexy are still under
investigation.4042 The atonia of REM sleep is thought to be
due to inhibition of the spinal alpha motor neurons of the
anterior horn cells by glycine and gamma-aminobutyric acid
(GABA) secreted by spinal interneurons (see Fig. 241B).
The interneurons are activated directly by projections from
areas in the pons responsible for atonia or via an intermedi-
ate relay area in the ventral medulla. Glutamate is believed
to activate the spinal interneurons. The atonia neurons of the
pontine reticular formation are located ventral to the locus
coeruleus and are often called the subcoeruleus (SubC) or
sublaterodorsal nucleus (SLD). The neurons are believed to
be glutaminergic. During REM sleep, there also appears to
be inhibition of pathways normally promoting alpha motor
neuron activity.
Cataplexy and the atonia of REM sleep may share some
common pathways, but there are important differences. John
and colleagues41 reported that histaminergic neurons in the
ventral posterior lateral hypothalamus remain active during
cataplexy as opposed to REM sleep (Fig. 242). Because his-
tamine is associated with wakefulness, this may at least par-
tially explain why patients remain conscious during cataplexy
but not REM sleep. The other important difference between
REM-associated atonia and cataplexy is the triggering emo-
tional stimulus for cataplexy. Neural pathways involving the
amygdala are thought to be important for the emotional
induction of cataplexy.
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 Chapter 24 Hypersomnias of Central Origin 455

8 1.6 1.6

Discharge rate (Hz)

Discharge rate (Hz)

Discharge rate (Hz)

6 1.2 1.2

4 0.8 0.8

2 0.4 0.4

0 0 0
AW QW NREM REM CAT AW QW NREM REM CAT AW QW NREM REM CAT
Posterior hypothalamus Dorsal raphe Locus coeruleus
(REM-off neurons) (REM-off neurons) (REM-off neurons)
(histamine) (serotonin) (noradrenergic)

FIGURE 242 Posterior hypothalamic (histaminergic) neurons remained active during cataplexy (CAT) whereas dorsal raphe (serotonergic) reduced discharge and
locus coeruleus neurons (noradrenergic) nearly ceased discharge. Note the difference between rapid eye movement (REM) and cataplexy for posterior hypothalamic
neurons and dorsal raphe neurons. AW = active wake; NREM = nonrapid eye movement; QW = quiet wake. From John J, Wu MF, Boehmer LN, Siegel JM: Cataplexy-
active neurons in the hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 2004;42:619634.

REM sleep

W
Sleep stage

R
Normal

N1
N2
NS
1800 2000 2200 2400 0200 0400 0600 0800 1000 1200 1400 1600
Time of day

REM sleep

W
Sleep stage
Narcolepsy

R
N1
N2
NS
1800 2000 2200 2400 0200 0400 0600 0800 1000 1200 1400 1600
Time of day
Normal and narcoleptic 24-h PSG recordings

FIGURE 243 Hypnogram of a normal individual and a patient with narcolepsy. Sleep and rapid eye movement (REM) periods were noted
throughout the day in the patient with narcolepsy. PSG = polysomnography. From Rogers AE, Aldrich MS, Caruso CC: Patterns of sleep and
wakefulness in treated narcolepsy subjects. Sleep 1994;17:590597.

Manifestations of Narcolepsy
inappropriate situations. Napping is usually restorative but
Similarities and differences between N+C, NC, and IH are provides only temporary relief. It has been said that falling
outlined in Table 24-3. IH is discussed in detail in a later asleep while standing or eating is especially suggestive of
section. narcolepsy. Even though patients may sleep at every hour of
the day, the total sleep time over a 24-hour period is normal
Excessive Daytime Sleepiness (N+C and NC) or only slightly increased.44,45 Rogers and associates44 per-
The EDS of narcolepsy can occur as discrete sleep attacks formed 24-hour polysomnography (PSG) in a group of nar-
or as constant sleepiness with intermittent worsening. Unre- colepsy patients who were well controlled. Of 25 subjects
lenting EDS is usually the first and most prominent symptom with narcolepsy, 10 had no daytime sleep but the other 14
of narcolepsy.14,43 Sleepiness may occur throughout the averaged 2.7 naps and 76.2 minutes of sleep during the day
day, regardless of the amount or quality of prior nighttime (compared with 4.8 min for controls).44 The two groups did
sleep. Sleep episodes may occur at work and social events, not differ in the total amount of sleep or the total amount of
while eating, talking, and driving, and in other similarly REM sleep in 24 hours. Figure 243 compares the 24-hour
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456 Chapter 24 Hypersomnias of Central Origin

TABLE 243
Features of Narcolepsy Syndromes versus Idiopathic Hypersomnia
N+C NC IH
SYMPTOMS
Daytime sleepiness Yes Yes Yes
Hypnagogic hallucinations (%) 7086 1560 40
Sleep paralysis (%) 5070 2560 4050
POLYSOMNOGRAPHY
Sleep latency Short Short Variable
Nocturnal REM latency < 15 min 33%
24%
Normal REM latency
Disturbed nighttime sleep Yes Yes No
Sleep efficiency (%)* 81 91 93
Stage N1 sleep Increased Mildly increased Normal
24-hr total sleep time Normal to slight Normal to slight Very increased in patients with
increase increase IH with long sleep time
MSLT
Mean sleep latency (min) 2.7 3.5 6.2 3.0
Sleep-onset REM periods (N) 2 2 01
(33.7 SOREMPs) (23.3 SOREMPs)
DQB1*0602 (% positive) 90100 4060 52
CSF hypocretin-1 Undetectable in 9095% Normal in 90% Normal
10% normal Reduced in 510%
Neuropathology Marked reduction in Unknown Unknown
hypocretin neurons
Body mass index Increased in 515% Normal Normal
*Sleep efficiency = total sleep time/total recording time.

From Aldrich MS, Chervin RD, Malow BA: Value of the multiple sleep latency test (MSLT) for the diagnosis of narcolepsy. Sleep 1997;20:620629.

From Arand D, Bonnet M, Hurwitz T, et al: A review by the MSLT and MWT Task Force of the Standards of Practice Committee of the AASM. The clinical use of the
MSLT and MWT. Sleep 2005;28:123147.

From Scammel TE: The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003;53:154166.
CSF = cerebrospinal fluid; IH = idiopathic hypersomnia; MSLT = multiple sleep latency test; N+C = narcolepsy with cataplexy; NC = narcolepsy without cataplexy;
REM = rapid eye movement; SOREMPs = sleep-onset rapid eye movement periods.
Adapted from Scammel TE: The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003;53:154166, with permission.

hypnograms of a patient with narcolepsy and a normal
subject. The hypnogram shows sleep episodes scattered
throughout the day, and some of the daytime sleep episodes
contain REM sleep.
In a study comparing narcoleptics and normal subjects
using 24-hour ambulatory monitoring, Broughton and
coworkers45 found no increase in the total amount of sleep
in 24 hours. However, narcoleptics had more daytime and
less nighttime sleep than normal persons.
Sleep-Related Hallucinations (N+C and NC)
The sleep-related hallucinations of narcolepsy that occur at
nocturnal sleep onset are called hypnagogic hallucinations
(HGHs) and those on awakening are termed hypnopompic
hallucinations (HPHs). The hallucinations are typically
bizarre and may be frightening. Patients sometimes have a
fair degree of insight that they are hallucinatory in nature,
but often consider them no less frightening. The duration is
usually less than 10 minutes, and the frequency is quite vari-
able. Visual imagery is the predominant feature for many
patients, sometimes with intense colors. A commonly
described vision is that of an animal or stranger in the room.
Auditory or vestibular hallucinations (sensation of falling)
may also occur. The percentage of narcolepsy patients report-
ing sleep-related hallucinations varies from 20% to 70%
depending on whether data are obtained from questionnaire
or physician interview.24 A questionnaire study by Aldrich4
found the proportion of N+C patients reporting sleep-related
hallucinations was higher than in the NC or IH groups.
Sleep-related hallucinations (especially HPH) can be associ-
ated with SP (discussed in the next section) and can also
occur in normal individuals.
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Sleep Paralysis (N+C and NC)
SP is partial or complete paralysis during the onset of sleep
or upon awakening. Patients are awake and conscious during
the attack. There is no emotional precipitant. The episodes
may last longer than a typical cataplectic attack. People who
experience SP sometimes experience hallucinations simulta-
neously. Studies have found that up to 50% to 80% of patients
with N+C report SP, with a lower percentage in the NC
group.4,43
Adequate ventilation is maintained during SP because
diaphragmatic function is spared. However, some patients
have a sensation of dyspnea. SP is often very frightening
owing to the inability to move, speak, or communicate
during the episode. SP is also reported in patients with sleep
apnea and occasionally in normal subjects especially after
periods of sleep deprivation. A syndrome of isolated recur-
rent SP (narcolepsy not present) exists and can be very
problematic for affected individuals.
Disturbed Nocturnal Sleep and Other Symptoms:
N+C, NC
Although HH/HPH, SP, and daytime sleepiness are the
classic narcolepsy symptoms, patients often report other
associated symptoms that can be significant (see Table 241).
Narcolepsy patients often experience disturbed nighttime
sleep with tossing and turning in bed, leg jerks, nightmares,
and frequent awakenings. The amount of stage N1 sleep is
increased. In general, N+C patients have more disturbed
sleep than NC patients.14 Automatic behavior is present
in up to 50% of patients. Automatic behavior is defined as
performing a seemingly purposeful task with no clear
memory of having performed the activity. For example,
patients report driving a car and not remembering the trip.
They may find themselves doing activities that make no sense
like putting salt in iced tea. These episodes typically involve
activities that are habitual or not demanding of skill.
Inattentiveness related to drowsiness may occur. Aldrich4
reported that the proportions of patients reporting automatic
behavior were similar in groups of N+C and NC patients.
Patients with narcolepsy may also have the rapid eye move-
ment sleep behavior disorder (RBD).46 In this disorder,
skeletal muscle atonia is absent during REM sleep and
dreams may be acted out. Because the Hcrt system has affects
on appetite, it is not surprising that some patients with N+C
have an increased body-mass index.4,47 Obstructive sleep
apnea (OSA) is also not uncommon.48 If cataplexy is not
present in a patient with OSA, narcolepsy may be suspected
only if daytime sleepiness persists after adequate treatment
of the sleep apnea. Periodic leg movements in sleep (PLMS)
are also common in narcolepsy.49 PLMS may be present
during REM sleep, a feature uncommon in most patients
with PLMS.
CATAPLEXY: N+C
As the name implies, cataplexy is an essential criterion for
the diagnosis of N+C. Cataplexy is the only symptom
Chapter 24 Hypersomnias of Central Origin 457
relatively specific to narcolepsy.14,50 Isolated cataplexy or
cataplexy with sleepiness (secondary narcolepsy) can occur
in a few rare neurologic disorders associated with mental
retardation and obvious neurologic deficits. These are dis-
cussed in a later section. In a patient with daytime sleepiness
and a normal neurologic examination, cataplexy is virtually
diagnostic of narcolepsy.
Cataplexy is characterized by the sudden, temporary loss
of bilateral muscle tone with preserved consciousness trig-
gered by strong emotions such as laughter, anger, or sur-
prise.43,50 After cataplexy episodes, patients have total recall
of the entire event. If the episodes last longer than a few
minutes, the patient may transition into REM sleep and
experience HHs. A systematic survey of symptoms of muscle
weakness associated with emotion in a large group of patients
with daytime sleepiness found that weakness during joking
(telling or hearing a joke), laughter, and anger were the
most specific for cataplexy associated with narcolepsy.43,50
Involvement of the legs also seemed to be more specific for
narcolepsy.
When loss of muscle strength during cataplexy is severe,
almost all of the voluntary muscles in the body are affected,
leading to complete collapse. The muscles of the eyes are not
affected during cataplexy; individuals can move their eyes
during a cataplectic episode. Diaphragmatic activity is also
not impaired. In one study, the legs and knees were most
frequently affected during cataplexy.50 In milder cases of
cataplexy, the loss in muscle strength can be quite subtle,
involving only a few muscle groups or occurring unilater-
ally. For example, ptosis, difficulty speaking, or partial neck
muscle weakness may occur (head nodding). In some
patients, partial attacks are more frequent than complete
attacks. Loss of muscle function may not be evident, and the
patient may experience only a vague feeling of weakness.
Patients may fall to the ground, and injuries do occur.
However, most people are able to find support at the onset
of an attack. The attacks do start abruptly but usually take
several seconds to reach their maximum intensity. Episodes
of cataplexy usually last from seconds to minutes; rarely does
an attack last longer than 2 minutes. Clinical signs during an
attack are the loss of muscle tone and loss of deep tendon
reflexes including a loss or decrease in the H reflex. During
an attack of cataplexy, there are cardiovascular changes con-
sisting of increased blood pressure and decreased heart rate.
The phenomenon of virtually continuous attacks of cataplexy
(status catapleticus) can occur after sudden withdrawal of
medications that suppress cataplexy.
DIAGNOSTIC TESTING FOR NARCOLEPSY
History
Patients with daytime sleepiness are invariably questioned
about SP, HH/HPHs, and the severity and nature of the
daytime sleepiness. However, none of these historical ele-
ments is specific for narcolepsy and they can occur in sleep
apnea and other causes of daytime sleepiness including IH4
(Table 244). A history of cataplexy is the most important
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458 Chapter 24 Hypersomnias of Central Origin
TABLE 244
Multiple Sleep Latency Test and Narcolepsy Facts
Diagnostic criteria: MSL 8 min.
2 SOREMPs in 5 naps.
MSLs
Narcolepsy 3.1 2.9 min.
Idiopathic hypersomnia 6.2 3.0 min.
Normal 10.5 4.6 min.
30% of the normal population has an MSL <8 min.
REQUIREMENTS FOR VALID MSLT
Previous PSG excluded causes of abnormal MSLT,
TST >360 min.
Free of drugs that influence sleep for 15 days (at least 5
times the drug half-life).
Standardized sleep schedule for at least 7 days
documented by actigraphy or sleep diary.
MSLs = mean sleep latencies; MSLT = multiple sleep latency test;
PSG = polysomnography; SOREMPs = sleep-onset rapid eye movement
periods; TST = total sleep time.
Data from references 1, 54, and 55.
symptom to elicit. In patients with EDS, unequivocal cata-
plexy, and a normal neurologic examination, a clinical diag-
nosis of narcolepsy can be made with some certainty. Even
if cataplexy is present, most physicians would still seek objec-
tive confirmation with PSG followed by a multiple sleep
latency test (MSLT).1 Daytime naps are often refreshing in
patients with narcolepsy. In contrast, naps are not commonly
refreshing in patients with IH.
Polysomnography
The nocturnal sleep study is used to rule out other significant
sleep disorders (sleep apnea) that might explain daytime
sleepiness. Nocturnal PSG often reveals a short sleep latency
and impaired sleep quality with increased stage N1 sleep and
decreased stage N3 sleep. The total sleep time may be reduced
but the amount of REM sleep is usually normal.51,52 Patients
with N+C on average have lower sleep efficiency, lower
amounts of stage N3 sleep, more stage N1 sleep, and more
awakenings than those with NC.2,4 PLMS are common in
patients with narcolepsy.49,52 Sleep-onset rapid eye movement
sleep (SOREM) is defined as a REM latency less than 15
minutes. Aldrich and colleagues53 found that 33% of N+C,
24% of NC, and 1% of SRBD patients had a SOREM on
nocturnal PSG. Of interest, the finding of a SOREM period
on the nocturnal PSG had a 98.5% specificity and 68% posi-
tive predictive value (true positives/total number of posi-
tives) for the diagnosis of narcolepsy. Therefore, although a
minority of patients with narcolepsy have a nocturnal
SOREMP (sleep-onset rapid eye movement period) on a
given PSG, the finding is highly suggestive of narcolepsy.
TABLE 245
Multiple Sleep Latency Test Findings in Patients
Evaluated for Daytime Sleepiness
N+C NC* SRBD
N 106 64 1251
MSL <5 min 87% 81% 39%
MSL <8 min 93% 97% 63%
2 SOREMPs 74% 91% 7%
2 SOREMPs + MSL <5 min 67% 75% 4%
2 SOREMPs + MSL <8 min 71% 91% 6%
SOREMPs on PSG 33% 24% 1%
*Diagnosis made in patients with NC by repeat MSLT if initial test
negative.
MSL = mean sleep latency; N+C = narcolepsy with cataplexy;
NC = narcolepsy without cataplexy; PSG = polysomnography;
SOREMPs = sleep-onset rapid eye movement periods; SRBD = sleep-related
breathing disorder.
Adapted from Aldrich MS, Chervin RD, Malow BA: Value of the multiple sleep
latency test (MSLT) for the diagnosis of narcolepsy. Sleep 1997;20:620629.
This is especially true if no other factor is present to
explain the short REM latency such as depression, OSA,
recent withdrawal of REM-suppressing medication, or sleep
deprivation.
Multiple Sleep Latency Test
The MSLT is the standard objective test for the assessment
of sleepiness and the diagnosis of narcolepsy5355 (Table
245; see also Table 244). Overnight PSG during the
patients habitual sleep period should precede the MSLT.
The purpose of the PSG is to exclude other causes of exces-
sive daytime sleepiness such as OSA and periodic limb
movement disorder (PLMD). A sleep diary or actigraphy
should document a regular and sufficient amount of sleep
for at least 7 days before the study. Medications that can
alter sleepiness (stimulants) or REM sleep should be with-
drawn at least 15 days before testing. REM-suppressing
medications can alter the ability to detect REM sleep.
However, acute withdrawal of REM-suppressing agents can
cause a false-positive test.
The ICSD-2 criteria for the diagnosis of narcolepsy
include a mean sleep latency of 8 minutes or less and two
or more SOREMPs during five naps.1 Aldrich and col-
leagues53 found that the MSLT had improved sensitivity
when a sleep latency of 8 minutes rather than 5 minutes was
used as a criterion for sleep latency in patients with NC. A
meta-analysis found the mean sleep latency for narcolepsy
patients to be 3.1 2.9 minutes.54,55 Up to 30% of the general
population have a mean sleep latency less than 8 minutes.
However, the finding of two or more SOREMPs is much
more specific for narcolepsy. Up to 2% of the normal popu-
lation will have two SOREMPs, and in other studies, approxi-
mately 6% of patients with SRBDs will have a mean sleep
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latency less than 8 minutes with two SOREMPs on an
MSLT.53,56 A few patients with narcolepsy will occasionally
have a mean sleep latency above 10 minutes. However, the
mean sleep latency is less than 5 minutes in the vast majority
of patients with narcolepsy (Fig. 244). The mean sleep
latency in patients with SRBDs tends to be higher than in
narcolepsy, although overlap does occur.
Unfortunately, the MSLT is not very sensitive or com-
pletely specific for the diagnosis of narcolepsy. Aldrich and
colleagues53 reviewed MSLT findings in patients evaluated
for daytime sleepiness (see Table 245). A diagnosis of nar-
colepsy in patients without cataplexy required a repeat MSLT
in some cases. In patients with N+C, a single MSLT was
positive only about 70% of the time. Hence, a negative MSLT
does not rule out the diagnosis of narcolepsy. In patients
ultimately believed to have only an SRBD, approximately 6%
had a positive MSLT53,56 (see Table 245).
It is recommended that sleep apnea be treated adequately
before an MSLT is performed to evaluate for narcolepsy.
Thus, successful treatment with continuous positive airway
pressure (CPAP) should be accomplished for several weeks.
Then, the patient should undergo a repeat PSG on CPAP
(documenting adequate treatment and sleep) and a subse-
quent MSLT. If good control of sleep apnea is demonstrated
during the night study but the MSLT meets criteria for nar-
colepsy, one can make a diagnosis of narcolepsy. This assumes
adequate adherence to CPAP has been documented. In this
setting, most clinicians perform the MSLT with the subjects
wearing CPAP.
HLA Typing
Although a high percentage of patients with N+C are posi-
tive for the HLA DQB1*602 antigen, this test is not very
140
120
100
Number of studies
80
60
40
20
0 than one third of the mean of normal values.
0 4 8 12 16 20
Mean sleep latency (min)
Narcolepsy Sleep-related
breathing disorder
FIGURE 244 Distribution of mean sleep latency (MSL) results for groups of patients
with narcolepsy and sleep-related breathing disorders. Although considerable overlap
is noted, patients with narcolepsy tend to have much lower MSL. From Aldrich MS,
Chervin RD, Malow BA: Value of the multiple sleep latency test (MSLT) for the diagnosis of
narcolepsy. Sleep 1997;20:620629.
Chapter 24 Hypersomnias of Central Origin 459
useful for ruling in narcolepsy (for either N+C or NC). The
HLA DQB1*602 is found in 12% to 38% of the general popu-
lation. Therefore, a positive result does not rule in N+C.
Conversely, a negative test for presence of DQB1*0602 is not
useful because up to 10% of N+C patients and 40% to 60%
of NC patients are negative for the antigen.1,2,13,57
CSF Hcrt Levels
Hcrt1 levels of the CSF can be assayed at a few centers. In
patients with N+C, over 90% have very low or undetectable
Hcrt1 levels. In one study of patients with many neurologic
diseases, only patients with N+C and a few patients with
Guillain-Barr had undetectable Hcrt levels.58,59 Patients with
a number of neurologic diseases had levels that were lower
than normal but still detectable. As noted previously, patients
with NC usually have normal levels of CSF Hcrt1. However,
about 10% of NC patients have low CSF Hcrt1. Most of
these NC patients with low CSF Hcrt1 are positive for the
HLA DBQ1*602.5860
Diagnostic Criteria and Important Findings for
N+C and NC Forms of Narcolepsy
Narcolepsy with Cataplexy (N+C) The ICSD-2 diagnostic crite-
ria for N+C1 are listed in Box 242. EDS for at least 3 months
BOX 242
Narcolepsy with CataplexyDiagnostic Criteria
A. The patient has a complaint of excessive daytime
sleepiness occurring almost daily for at least 3 months.
B. A definite history of cataplexy defined as sudden and
transient episodes of loss of muscle tone triggered by
emotions is present.
Cataplexy = episodes must be triggered by strong
emotionmost reliably laughing or jokingand must be
bilateral and brief (<2 min). Consciousness must be
preserved (at least in the beginning)
Strong evidence = observed cataplexy with loss of DTRs.
C. The diagnosis of narcolepsy with cataplexy should,
whenever possible, be confirmed by nocturnal PSG
followed by an MSLT with a mean sleep latency less
than or equal to 8 minutes with two or more SOREMPs
observed following sufficient nocturnal sleep (minimum
of 6 hr) during the night prior to the test.
Alternatively: CSF hypocretin-1 level <110 pg/mL or less
D. Hypersomnia is not better explained by another sleep
disorder, medical or neurologic disorder, medication, or
substance use disorder.
CSF = cerebrospinal fluid; DTRs = deep tendon reflexes; MSLT = multiple
sleep latency test; PSG = polysomnography; SOREMPs = sleep-onset rapid
eye movement periods.
From American Academy of Sleep Medicine: International Classification of
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
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460 Chapter 24 Hypersomnias of Central Origin
is required along with cataplexy. When possible, the diagno-
sis should be confirmed by an MSLT (sleep latency 8 min
and two or more SOREMPs). A low CSF Hcrt1 level is con-
sidered confirmatory even in the absence of an MSLT
meeting diagnostic criteria. Other sleep disorders causing
the abnormal MSLT should be excluded.
N+C Manifestations Whereas only daytime sleepiness and
cataplexy are required to make the diagnosis of N+C, other
manifestations such as sleep-related hallucinations, SP, and
automatic behavior are often present (see Table 241). Only
10% to 15% of patients have the classic symptom tetrad of
daytime sleepiness, cataplexy, HGH/HPHs, and SP. Patients
with N+C tend to have a higher frequency of SP, HHs, and
more severe sleepiness than NC patients. During PSG, sleep
is more disturbed in N+C patients than in NC patients. On
the MSLT, N+C patients tend to have more SOREMPs.
Although 90% of N+C patients are positive for DQBQ1*602,
this is not useful diagnostically.
Onset of N+C The manifestations of N+C generally begin
between the ages of 15 and 30 years.43 However, this form of
narcolepsy can present in the pediatric age group or in
patients older than 60 years. EDS alone or in combination
with HHs and/or SP is the presenting symptom in approxi-
mately 90% of patients.43 Cataplexy may develop several
years after symptoms begin. However, most patients with
N+C develop cataplexy within 3 to 5 years of the onset of
daytime sleepiness.14,43 Rarely, cataplexy can precede daytime
sleepiness.
Polysomnography Typical findings include a short sleep
latency and approximately 20% to 30% have a short noc-
turnal REM latency.53 Of interest, in one study, the pres-
ence of sleep-onset REM during the nocturnal sleep study
had a high positive predictive value for the presence of
narcolepsy.53 There tends to be an increase in stage N1
sleep.
Multiple Sleep Latency Test Approximately 70% of patients with
N+C will have a MSLT meeting criteria for narcolepsy. The
mean sleep latency tends to be slightly less in N+C than in
NC patients and SOREMPs are slightly more frequent than
in patients with NC (see Table 243).
Other Studies in N+C
1. Absent to low Hcrt1 in the CSF fluid (90100%).
2. Absence of Hcrt-staining cells in the hypothalamus.
3. Ninety percent are positive for DQBQ1*602 antigen.
Narcolepsy without Cataplexy (NC)
The ICSD-2 diagnostic criteria for NC are listed in Box
243. Daytime sleepiness must be present for at least 3
months but typical cataplexy is NOT present. An MSLT
shows a mean sleep latency of 8 minutes or less and two or
more SOREMPs. The other manifestations of narcolepsy
including SP, HHs, and automatic behavior may or may not
BOX 243
Narcolepsy without CataplexyDiagnostic Criteria
A. Complaint of excessive daytime sleepiness almost daily
for at least 3 months.
B. Typical cataplexy is not present.
C. Nocturnal PSG followed by MSLT findings:
MSLT less than or equal to 8 min.
Two or more SOREMPs (MSLT)
Sufficient nocturnal sleep (at least 6 hr).
D. Hypersomnia is not better explained by another sleep
disorder, medical or neurologic disorder, medication, or
substance use disorder.
MSLT = multiple sleep latency test; PSG = polysomnography;
SOREMPs = sleep-onset rapid eye movement periods.
From American Academy of Sleep Medicine: International Classification of
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
be present. Compared with patients with N+C, a lower per-
centage of patients with NC report SP or HH (see Table
243).2
Polysomnography (NC) NC patients have a short nocturnal
sleep latency and 20% to 30% have a short nocturnal
REM latency.53 The amount of stage N1 sleep is increased.
NC patients tend to have less disturbed sleep than N+C
patients.
MSLT Findings (NC) The findings are similar to those of N+C
patients. However, there may be a slightly longer mean sleep
latency and fewer SOREMPs. Patients with NC tend to have
milder sleepiness and fewer numbers of naps with sleep-
onset REM sleep compared with N+C patients. Unfortu-
nately, as discussed previously, an MSLT meeting criteria for
the diagnosis of narcolepsy is not completely sensitive or
specific. If clinically indicated, repeat testing could be needed.
This is in contrast to patients in whom definitive cataplexy
is present. A diagnosis of N+C can be made even if the MSLT
does not meet criteria if daytime sleepiness and unequivocal
cataplexy are present.
TREATMENT OF NARCOLEPSY
The treatment of narcolepsy is usually broken into two com-
ponents: (1) treatment of EDS and (2) treatment of cataplexy,
SP, and HGH/HPHs.6164
Treatment of EDS
The treatment of daytime sleepiness includes conservative
measures (adequate sleep time, good sleep hygiene, sched-
uled daily naps65), stimulant medications, alerting medica-
tions, and sodium oxybate (Table 246). Adequate control of
daytime sleepiness can be attained in about 60% to 80% of
patients. The stimulant medications used to treat the daytime
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 Chapter 24 Hypersomnias of Central Origin 461

TABLE 246
Medications Used to Treat Excessive Daytime Sleepiness
MEDICATION MAXIMUM
(FDA PREGNANCY BRAND DOSE HALF-LIFE SELECTED SIDE
CATEGORY) NAME DOSE (DAILY) (hr) EFFECTS
Methylphenidate* Ritalin 1030 mg bid or 1020 mg 100 mg 24 Nervousness,
(C) tid (5, 10, 20 mg tabs) tremulousness,
headache
Methylphenidate SR Metadate 1020 mg SR qAM (10, 20 mg
and others tabs) + 10 to 20 mg
Concerta short-acting in afternoon
1836 mg SR qAM (18, 27, 36,
54 mg tabs) + 10 to 20 mg
short-acting in afternoon
Dextroamphetamine* Dexedrine 560 mg qd 60 mg 1030 Nervousness,
(C) Dextrostat 530 mg bid tremulousness,
and others (5, 10 mg tabs) headache
Amphetamine/ Adderall (5, 7.5, 12.5, 15 mg tabs)
dextroamphetamine
Dextroamphetamine SR 10 mg SR qAM
SR 5, 10, 15 mg tabs
+10 to 20 mg short-acting in
afternoon
Amphetamine/ Adderall XR 5, 10, 15, 20, 25, 30 mg
dextroamphetamine capsules
XR
Methamphetamine* Desoxyn 5 to 60 mg qd (5, 10 mg 60 mg 1234 Nervousness,
(C) tabs) tremulousness,
headache
Lisdexamfetamine Vyvanse 20, 30, 40, 50, 60 mg 70 mg 1213 Nervousness,
dimesylate* (duration of tremulousness,
(C) action) headache
Modafinil Provigil 200 or 400 mg qd (100, 400 mg 914 Headache, drug
(C) 200 mg tabs) interactions,
nervousness
Armodafinil Nuvigil 150250 mg daily 250 mg 1014 Headache, drug
(C) 150, 250 mg tabs interactions,
nervousness
Sodium oxybate Xyrem 4.59 g/night in 2 divided 9g 13 Sedation, enuresis,
(B) doses respiratory suppression
Selegiline Eldepryl 2040 mg 40 mg 914 Nausea, dizziness,
(C) confusion, dry mouth,
requires low-tyramine
diet, drug interactions
FDA approved for treatment of EDS in narcolepsy: modafinil, armodafinil, dextroamphetamine, methylphenidate, sodium
oxybate.
Black box warnings:
Stimulants: Abuse potential.
Sodium oxybate: Abuse potential, should not be used with alcohol or other CNS depressants.
*Schedule II medication (no refills, no telephone prescriptions).

Schedule IV medication.
CNS = central nervous system; EDS = excessive daytime sleepiness; FDA = U.S. Food and Drug Administration; SR = sustained release.
B and C: Pregnancy category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in
pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to
the fetus in any trimester. Pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-
controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

DaneshGroup.com
462 Chapter 24 Hypersomnias of Central Origin

sleepiness of narcolepsy include amphetamine (racemic), dextroamphetamine, and the highest postdrug values were
dextroamphetamine, methamphetamine, and methylpheni- for methylphenidate (although baseline values were the
date. Dextroamphetamine and methylphenidate are U.S. highest for this medication). No medication came close to
Food and Drug Administration (FDA) approved for treat- normalizing objective sleepiness.
ment of narcolepsy. A mixture of amphetamine and
dextroamphetamine (~25% L-amphetamine and 75% Stimulant Medications
D-amphetamine) is also available (Adderall). Some patients The stimulant medications increase dopamine transmission
respond best to a mixture, although D-amphetamine may by presynaptic mechanisms. The medications inhibit the
cause less anxiety. Methamphetamine is effective but has a reuptake of dopamine (DA) and, to a lesser extent, NE and
high abuse potential. The FDA does not list narcolepsy as an serotonin by the dopamine transporter (DAT).6770 The
indication for methamphetamine. The stimulant medica- action of amphetamines on DAT causes a reverse efflux of
tions are indirect sympathomimetic stimulants (increase the DA through the site as well as blocking reuptake. The
synaptic availability of dopamine and norepinepherine). amphetamines also inhibit cytoplasmic vesicular storage of
Modafinil and its R enantiomer armodafinil are two DA by the vesicular monoamine transporter (VMAT2). In
alerting medications that are FDA approved for treatment contrast, methylphenidate has no effect on DA storage. The
of daytime sleepiness in narcolepsy. There are no studies overall action of the stimulant medications is to increase the
directly comparing the efficacy of stimulant and alerting synaptic levels of DA.
medications. However, the relative objective improvement The peak action of dextroamphetamine, methamphet-
in the sleep latency after medication on the MSLT or main- amine, and methylphenidate is 1 to 3 hours from ingestion,
tenance of wakefulness test (MWT) has been compared so the medications should be taken at least 1 hour before the
by computing the pre- and postdrug sleep latency values time of desired effectiveness. If a sleep attack has begun
as a percentage of normal for the test66 (Fig. 245). Because before medication is taken, a nap may be the best treatment
the predrug values differ between the studies, the change in some patients. Also note that methylphenidate has a much
from baseline of drug is the main effect of interest. The shorter half-life than dextroamphetamine and methamphet-
relative improvements in objective sleepiness are displayed amine (see Table 246) and must be taken several times a
by normalizing the pretreatment (gray bars) and post- day (bid to tid). Sustained-action forms of the amphetamines
treatment (green bars) values of the sleep latency on the and methylphenidate are available. Of note, stimulant medi-
MWT or MSLT as a percentage of the published normal cations may have a mild beneficial effect on cataplexy but
values for the MSLT (13.4 min) or the MWT (18.9 min). modafinil has no effect on cataplexy.
The largest changes were for methamphetamine and The side effects of the stimulant medications include ner-
vousness, headache, loss of appetite, palpitations, irritability,
and tremor. All of these medications are schedule II drugs
100 (requiring monthly prescriptions). There are several poten-
Baseline
90 Treatment tial problems with the use of stimulant medications.66,67 First,
Sleep latency (% of normal)

80 tolerance may develop (documented by some but not all

(MWT)
70 (MSLT) studies), requiring escalating doses and leading to ineffec-
(MWT)
60 tiveness at the highest dose. In some patients, effectiveness
(MWT) (MWT) can be restored by a drug holidayno medications for
50
40 several days. Unfortunately, severe sleepiness may occur
30 during that time. Second, the medications can increase blood
20 pressure, although this effect is not usual in normotensive
10 patients.71 Third, insomnia is a common side effect of stimu-
0 lants. Thus, they should not be taken near bedtime, especially
Normal methamphetamine and dextroamphetamine, both of which
Dextroamphetamine
Pemoline

Modafinil

Methamphetamine

Methylphenidate

have a relatively long half-life. Fourth, attacks of paranoia or

hallucinations have been reported with amphetamines, but
major psychiatric side effects are rare in the absence of
underlying psychiatric disorders.72 However, use of very high
doses of stimulants is associated with an increased risk of
adverse outcomes.72
FIGURE 245 Comparison of the effects of stimulant medications and modafinil on
Methylphenidate appears to have a lower propensity to
sleep latency (multiple sleep latency test [MSLT] or maintenance of wakefulness test
[MWT]). The pre- and postdrug values were normalized as a percentage of accepted
produce side effects and is probably the most widely used
normal values for the tests MSLT (13.4 min) or MWT (18.9 min). The dose of drugs used stimulant medication. However, the relatively short duration
was 112.5 mg for pemoline, 300 mg for modafinil, 60 mg for dextroamphetamine, of action of methylphenidate is sometimes problematic
60 mg for methylphenidate, and 4060 mg for methamphetamine. From Mitler M, because patients may experience a sudden decrease in alert-
Aldrich MS, Koob GF, et al: ASDA standards of practice: narcolepsy and its treatment with ness as the medication wears off. One treatment approach is
to use sustained-action forms of methylphenidate in the
stimulants. Sleep 1994;17:352371.
DaneshGroup.com

morning with short-acting forms in the afternoon or evening.
In some patients, a small dose of short-acting methylpheni-
date must also be added in the morning to help patients
more rapidly achieve alertness for early morning activity.
There are individual patients who will tolerate the slower
onset of sustained-action medications while they find the
shorter-acting medications intolerable (jittery or nervous).
The American Academy of Sleep Medicine (AASM) Practice
Parameters for Treatment of Narcolepsy and Other Hyper-
somnias of Central Origin61 stated combinations of long-
and short-acting stimulants may be indicated and effective
for some patients (Option). Lisdexamfetamine dimesylate
(Vyvanse) is a once-daily medication approved for treating
attention deficit hyperactivity disorder (ADHD) for ages 6
to 17 and adults. It is a prodrug that is converted to dextro-
amphetamine in the gastrointestinal tract. This medication
has also been used off label to treat narcolepsy (see Table
246).
Modafinil and Armodafinil
Modafinil and armodafinil (R entaniomer of modafinil) are
nonamphetamine wakefulness-promoting medications that
are schedule IV medications (refills and telephone orders
allowed). They are considered to have less abuse potential
than the stimulant medications. Modafinil is considered to
be the first-line medication for treatment of EDS associated
with narcolepsy.61,67,73 Randomized, placebo-controlled trials
have documented the effectiveness of modafinil in patients
with narcolepsy.7375
The elimination half-life of modafinil is 9 to 14 hours,
permitting once-daily administration for most patients.
Modafinil is usually administered once daily in the morning
(200400 mg). However, some patients taking modafinil in
the morning may experience poor control of daytime sleepi-
ness in the afternoon or early evening. They may respond to
split dosing (200 mg in AM, 200 mg at 12 PM).76,77 Although
the maximum recommended daily dose of modafinil is
400 mg, higher doses have been used. There are some
patients in whom adequate control of sleepiness may require
a slightly higher dose than 400 mg (400 mg in the AM and
200 mg in the early afternoon).76,77
The L enantiomer of modafinil has a shorter half-life
(34 hr) than the R enantiomer (1014 hr). Modafinil
(racemic, containing both L and R enantiomers) has a similar
terminal half-life as armodafinil. Within a few hours after
taking modafinil the only enantiomer left in the blood is
armodafinil.7880 If the same doses of modafinil and
armodafinil are given in the morning, the afternoon blood
levels of armodafinil are considerably higher. For this reason,
a morning dose of armodafinil (150250 mg) may control
afternoon sleepiness better than modafinil. A double-blind
study by Harsh and associates81 documented the efficacy and
safety of armodafinil.
There is no evidence that tolerance develops to modafinil
or that the drug impairs sleep quality (if taken in the
morning). It has a number of advantages including once-
daily dosing, low abuse potential, and the fact that it is not
Chapter 24 Hypersomnias of Central Origin 463
a schedule II medication. As noted previously, there are no
head-to-head studies comparing effectiveness of modafinil
and stimulant medications. However, when compared for
the ability to normalize the sleep latency, stimulant medica-
tions appear slightly more effective.66 Thus, although
modafinil is considered the drug of choice for daytime
sleepiness in patients with narcolepsy, some patients will
respond better to a stimulant.
The mechanism of action of modafinil is not known,67,8284
but the drug likely targets the DA reuptake system. The alert-
ing effect of modafinil is not specific to patients with narco-
lepsy. Modafinil does not bind the receptors or uptake sites
of NE, GABA, adenosine, or benzodiazepines. It does weakly
bind to the DAT.82 Modafinil does enhance the activity of
many brain sites associated with wakefulness including the
tuberomammillary nucleus and Hcrt cells of the periforni-
cal area.83 However, modafinil does not require the Hcrt
system to be effective. Modafinil can reduce the extracellular
GABA concentrations.84 Because GABA is an inhibitory
neurotransmitter, this could disinhibit a number of wake-
promoting sites such as the tuberomammillary neurons
(TMNs). Another possibility is that modafinil may increase
dopaminergic signaling. All the brain regions activated by
modafinil receive dopaminergic innervation.85 Wisor and
coworkers70 found that modafinil does not improve wakeful-
ness in mice lacking the DAT. As noted previously, modafinil
does bind weakly to the DAT. A study by Gallopin and col-
leagues85 found that modafinil blocks reuptake of NE by
noradrenergic terminals that interface with sleep-promoting
neurons of the ventrolateral preoptic nucleus (VLPO).
Higher NE at the VLPO would be wake-promoting because
NE inhibits the activity of the VLPO. The mechanism by
which modafinil blocks reuptake is unclear because modafinil
does not bind to NE receptors. After numerous investiga-
tions, the mechanism by which modafinil works is still
unknown.86 In summary, modafinil may promote NE and
dopaminergic transmission of wake-promoting centers.
Continued research in this area will likely help design more
effective treatments for narcolepsy.
The most common side effects of modafinil include head-
ache, nausea, and nervousness. Headache can be minimized
by a slow increase in dose. A few cases of severe skin rash
(Stevens-Johnson syndrome) have been reported in patients
taking modafinil (very low prevalence). Modafinil is metab-
olized in the liver by the cytochrome P-450 (CYP450) system.
Hence, a number of drug interactions are possible. The main
interaction of significance is that certain oral contraceptives
may be less effective after modafinil is started. Female
patients of reproductive age taking oral contraceptives
should use additional (or alternative) methods of contracep-
tion. Unlike the indirect sympathomimetics, withdrawal of
modafinil does not result in a rebound of REM and slow
wave sleep. Patients can be switched from stimulants to
modafinil without a washout period. However, because stim-
ulant medications have some anticataplectic action, patients
changed from methylphenidate to modafinil may require the
addition of specific medications for cataplexy.87
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464 Chapter 24 Hypersomnias of Central Origin

Sodium Oxybate (modafinil) or stimulants. A 4-week study demonstrated a

Gamma hydroxybutyrate (GHB) is naturally occurring in significant reduction in subjective sleepiness (Epworth
the CNS and acts as a neurotransmitter at two GHB receptor Sleepiness Scale) at the 9-g dose88 (Fig. 246). A 12-month
subtypes. In large doses, the drug acts at GABA-B receptors. extension trial showed continued administration of SOXB
It is tasteless and, when given in sufficient doses, can cause resulted in progressive improvements in EDS that were
rapid sedation and amnesia. This resulted in the compounds maximal after 2 months.89 A double-blind, placebo-controlled
use as the date rape drug. In sufficient doses, respiratory trial found that 9 g of SOXB nightly was associated with a
depression and death can occur. Sodium oxybate (SOXB) is greater than 10-minute median increase in the sleep latency
the sodium salt of GHB. It is a whitish crystalline powder on the MWT.90 Black and Houghton found that a combina-
that is highly soluble in water. SOXB (Xyrem) has been tion of modafinil and Xyrem was more efficacious than
proved to be effective for EDS in narcolepsy as well as for either taken alone in increasing the sleep latency on the
cataplexy.8893 Due to the potential for abuse, SOXB is avail- MWT (Fig. 247).91
able only from a single central pharmacy. SOXB is also effective at reducing cataplexy, HH/HPHs,
In many of the studies of SOXB in narcolepsy, patients and SP in patients with narcolepsy. This use is discussed in
were allowed to continue on their alerting medication a later section. It appears that somewhat higher doses of

FIGURE 246 Effect of sodium oxybate on subjective sleepiness 24

Placebo 3.0 g 6.0 g 9.0 g
in narcolepsy. Lines are median (circles) and 25th and 75th
B E B E B E B E
percentile (diamonds) values. At 9.0 g, the reduction was 22
significant (*) and the median was just above the normal range.
B = baseline; E = end of the study. From U.S. Xyrem Multicenter 20
Study Group: A randomized, double-blind, placebo-controlled
Epworth sleepiness score

multicenter trial comparing the effects of three doses of orally 18 Narcolepsy

administered sodium oxybate with placebo for the treatment of range
narcolepsy. Sleep 2002;25:4249. 16

14

12
*
10

8 Normal
range
6

Stable
modafinil
dose
14
MWT sleep latency (min)

13 Modafinil-sodium oxybate
12 (Placebo modafinil)-sodium oxybate
11
10 Modafinil-(Placebo sodium oxybate)
9
8
7 (Placebo modafinil)-(placebo sodium oxybate)
6
Visit 2 Visit 3 Visit 4 Visit 5

Sodium oxybate
increased to 9 grams

FIGURE 247 A combination of modafinil and sodium oxybate may be more effective than sodium oxybate alone in some patients.
After visit 4, one group was changed to placebo-modafinil, one group to placebo-sodium oxybate, one group to both placebo-
modafinil and placebo-sodium oxybate; one group continued on active medications. Both modafinil and sodium oxybate resulted in
a higher sleep latency compared with placebo-placebo. At visit 4, the highest latency was in the group with both active medications.
However, there was less benefit from the addition of modafinil at visit 5 after the dose of sodium oxybate was increased to 9 g. MWT
= maintenance of wakefulness test. From Black J, Houghton WC: Sodium oxybate improves excessive daytime sleepiness in narcolepsy.
Sleep 2006;29:939946.
DaneshGroup.com

SOXB may be needed to improve daytime sleepiness as
compared with cataplexy.92,93 The benefits on EDS may take
a few months for maximum effect. The FDA approved SOXB
for treatment of both daytime sleepiness and cataplexy.
SOXB is the only medication FDA approved for cataplexy.
The mechanism of action of SOXB with respect to reducing
daytime sleepiness is unknown. Studies have shown that the
medication reduces nocturnal awakenings and increases
stage N3 sleep and consolidates REM periods.94 Some have
hypothesized that sleep consolidation improves daytime
sleepiness.
SOXB (Xyrem) is available as a liquid (500 mg/mL) and,
because of a short half-life, must be taken at bedtime and
repeated 2.5 to 4 hours later. The drugs effect is so rapid that
after ingesting each dose of the medication, patients should
lie down and remain in bed. SOXB taken on an empty
stomach reaches peak concentrations in 0.5 to 1.5 hours and
has a half-life of 40 to 60 minutes. Each dose of medication
is diluted with 60 mL of water in the child-resistant dosing
cups. Both doses should be prepared before going to bed.
The dose in the middle of the night should be taken while
the patient is sitting in bed. It is very important to note that
food can reduce the bioavailability of SOXB. SOXB is
started at 4.5 g/night taken in divided doses (2.25 g taken at
bedtime and repeated 2.54 hr [usually ~3 hr] later). The
dose is then increased in 1.5-g/night increments each week
until a maximum of 9 g/night is reached. One might aim for
lower doses in smaller patients. If side effects are intolerable,
the dose can be decreased temporarily and then a trial at an
increased dose can be tried later. Nausea, dizziness, and
enuresis are the most common side effects. SOXB is associ-
ated with a high sodium load and this can be a significant
concern in patients with congestive heart failure. The simul-
taneous use of SOXB and alcohol or other CNS depressants
is contraindicated.
A study of 4 consecutive nights of SOXB in patients with
mild to moderate OSA not on CPAP found no significant
worsening in the apnea-hypopnea index (AHI) and mean
arterial oxygen saturation (SaO2).95 In this study, stage N3
increased but the number of central apneas also increased
and a few patients did experience significant oxygen desatu-
ration. Thus, although not an absolute contraindication,
SOXB should be used with caution in patients with OSA. If
SOXB is used in patients with very severe OSA, adequate
treatment of OSA (CPAP) is essential. It may be prudent to
perform nocturnal oximetry when SOXB treatment is started
or the dose is increased.
Other Interventions for Daytime Sleepiness
Another treatment alternative that can be tried in patients
not tolerating stimulants is the irreversible monoamine
oxidase (MAO) type B inhibitor selegiline. At doses of 10 to
40 mg/day, this drug has been shown to improve narcoleptic
symptoms.96 Unfortunately, at doses over 20 mg/day, it loses
its MAO B inhibitor selectivity and a low-tyramine diet
is indicated to avoid the risk of hypertensive reactions. Sege-
line is metabolized to amphetamine. The drug also has
Chapter 24 Hypersomnias of Central Origin 465
anticataplectic activity in addition to its alerting ability.
Patients who experience intolerable side effects with other
agents may benefit from this medication as long as they are
willing to adhere to a low-tyramine diet.
Improving nocturnal sleep and treatment of concurrent
sleep disorders is also important for improving daytime
sleepiness. Benzodiazepine receptor agonists may improve
sleep quality in some patients. If the restless legs syndrome/
PLMS are significantly impairing sleep, specific treatment for
these problems may be helpful. The combination of narco-
lepsy and OSA is commonly encountered. Adequate treat-
ment of OSA with nasal CPAP or other therapies is essential.
Good sleep hygiene with a regular sleep schedule and ade-
quate sleep is essential for narcolepsy patients. Some find
short scheduled naps to also be beneficial.
Choosing Treatment for Daytime Sleepiness
The AASM has recently published practice parameters
regarding the treatment of narcolepsy and central hypersom-
nias61 (Table 247). For daytime sleepiness, both modafinil
and SOXB received Standard recommendations. Due to
convenience and tolerability, most physicians would start
treatment with modafinil or armodafinil. If modafinil (or
armodafinil) is not sufficiently effective, one option is to
switch to a stimulant medication. A combination of short-
acting and long-acting methylphenidate may be better toler-
ated in some patients (methylphenidate 20 mg SR qAM and
1020 mg short-acting in early afternoon). Another option
for patients not responding to modafinil is to move directly
to SOXB (especially if cataplexy is significant). In some
studies, SOXB restored subjective sleepiness to the normal
range. However, SOXB is an expensive medication and
requires that the patient reliably follow instructions. In any
case, if both modafinil and stimulants are not effective, one
could prescribe SOXB. Often, modafinil (or stimulant medi-
cation) is continued as the dose of SOXB is increased. If
treatment of both daytime sleepiness and cataplexy is needed,
SOXB would be especially useful. Some patients do not toler-
ate alternative medications for cataplexy, and in this group,
SOXB is also a good option.
Treatment of Cataplexy, HGH/HPHs, and SP
In some patients with N+C, the episodes of cataplexy are so
uncommon or mild that treatment is not needed. In others,
they constitute an important problem for patients. The medi-
cations that are useful for the treatment of cataplexy also
suppress the other associated symptoms of narcolepsy
including SP and HGH/HPHs (Table 248). It should be
recalled that these phenomenon can occur in normal indi-
viduals and do not require treatment unless recurrent and
clinically significant. The classic medications useful in treat-
ing cataplexy have a common property of suppressing REM
sleep. In the canine form of narcolepsy, drugs increasing NE
are the most efficacious.97
The tricyclic antidepressants (TCAs) were the first group
used to treat cataplexy. The first agent used was imipramine,
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466 Chapter 24 Hypersomnias of Central Origin

TABLE 247 but other TCAs including protriptyline, desipramine, and

American Academy of Sleep Medicine Practice clomipramine have been used. They are commonly effective
Parameters for Treatment of Narcolepsy and in doses less than those used for antidepressant action. Pro-
Hypersomnia of Central Origin* triptyline, desipramine, and imipramine block reuptake of
NARCOLEPSY
NE, and clomipramine is a more potent blocker of serotonin
reuptake. The major problem with these medications is their
Daytime sleepiness Modafinil (Standard) anticholinergic side effects. For this reason, these drugs are
Sodium oxybate (Standard) not the first choice for treatment of cataplexy.
Amphetamine (Guideline)
The selective serotonin reuptake inhibitors (SSRIs) such
Methamphetamine (Guideline)
as fluoxetine have also been found useful in treating cata-
Dextroamphetamine (Guideline)
Methylphenidate (Guideline) plexy.98 The SSRIs (fluoxetine) are used in typical antidepres-
Selegiline (Option) sant doses and their effect may be more delayed than that of
the TCAs. However, because the SSRIs generally are better
Cataplexy Sodium oxybate (Standard)
tolerated and safer in overdose than TCAs, they are widely
Tricyclic antidepressants
used. The selective serotonin and norepinephrine reuptake
(Guideline)
SSRIs (Guideline) inhibitors (SNRIs) such as venlafaxine block the reuptake of
Venlafaxine (Guideline) both serotonin and NE. The extended-release formulation of
Selegiline (Option) venlafaxine is preferred because the drug has a short half-
life. The SNRIs appear to be particularly useful in treating
Sleep paralysis, Sodium oxybate (Option)
cataplexy and are generally well tolerated.67,87 Atomoxetine,
hypnagogic Tricyclic antidepressants (Option)
hallucinations due SSRIs (Option)
an adrenergic reuptake blocker used for ADHD, has also
to narcolepsy Venlafaxine (Option) been used as a treatment for cataplexy. Both venlafaxine
and atomoxetine can increase blood pressure. Selegiline
IDIOPATHIC HYPERSOMNIA
(Eldepryl) has also been used to treat cataplexy but, due to
Daytime sleepiness Modafinil (Option) its side effects and drug interactions, is rarely used.96
Amphetamine (Option) Although the previous medications were recommended
Methamphetamine (Option) as effective treatments for cataplexy (Guideline) by the recent
Dextroamphetamine (Option) AASM Practice Parameters for the Treatment of Narcolepsy
Methylphenidate (Option) and Hypersomnia of Central Origin, none of these medica-
MEDICAL DISORDERS ASSOCIATED WITH HYPERSOMNIA tions is FDA approved for cataplexy treatment. Abrupt ces-
Parkinsons disease Modafinil (Option) sation of anticataplectic medications can markedly worsen
cataplexy and result in nearly continuous attacks (status cata-
Myotonic dystrophy Modafinil (Option) plecticus). Consistent with the concept that medications that
Methylphenidate (Option)
increase NE are effective treatments for cataplexy, there has
Multiple sclerosis Modafinil (Guideline) been a report of exacerbation of cataplexy by the alpha-1
RECURRENT HYPERSOMNIA blocker prazosin.99
A portion of patients with narcolepsy do not respond well
Episodes (shorter Lithium (Option)
to the traditional medications used to treat cataplexy or are
duration, less
unable to tolerate the side effects. For these patients, SOXB
severe symptoms)
can be an effective option. SOXB is the only FDA-approved
Daytime sleepiness Modafinil (Option) treatment for cataplexy and has the additional advantage of
Amphetamine (Option) treating daytime sleepiness. The method by which the medi-
Methamphetamine (Option) cation decreases cataplexy is unknown. The dosage of SOXB
Dextroamphetamine (Option)
and side effects were previously discussed. The effectiveness
Methylphenidate (Option)
of SOXB in decreasing episodes of cataplexy has been
HYPERSOMNIA DUE TO MEDICAL CONDITION documented by placebo-controlled studies.61,88,92,93 SOXB
Daytime sleepiness Modafinil (Option) can improve cataplexy at lower doses (4.5 gm/night)93 than
Amphetamine (Option) daytime sleepiness, and the maximum effect takes a few
Methamphetamine (Option) months to be noted (Fig. 248).
Dextroamphetamine (Option)
Methylphenidate (Option)
*Evidence level: Standard > Guideline > Option.
Future Treatments for Narcolepsy
SSRIs = selective serotonin reuptake inhibitors.
A number of treatments targeting a proposed autoimmune
From Morgenthaler TI, Kapur VK, Brown TM, et al: Practice parameters for the
treatment of narcolepsy and other hypersomnias of central origin. Sleep mechanism have been tried in narcolepsy3,68,100,101 including
2007;30:17051711. steroids, plasma exchange, and immunoglobulins without
clear long-term benefit. Another approach would be admin-
istration of Hcrt or Hcrt analogues. Central administration
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 Chapter 24 Hypersomnias of Central Origin 467

TABLE 248
Medications Used for Treatment of Cataplexy, Hypnagogic Hallucinations, and Sleep Paralysis
DRUG (BRAND MAXIMUM HALF-LIFE
NAME) DOSE DOSE (DAILY) (hr) SELECTED SIDE EFFECTS
TRICYCLIC ANTIDEPRESSANTS
Protriptyline 510 mg bid or tid 30 mg 6789 Dry mouth, urinary hesitancy,
(Vivactil) (5-, 10-, 20-mg tabs) constipation
Clomipramine Start 50 mg qhs 250 mg 32 Dry mouth, sweating,
(Anafranil) (75125 mg) drowsiness
Imipramine Start 50 mg qhs 300 mg 620 Dry mouth, constipation,
(Tofranil) (75125 mg) drowsiness
SSRIS
Fluoxetine Start 20 mg qAM 80 mg 48216 Headache, dry mouth, sexual
(Prozac) (2060 mg) dysfunction
NSRIS
Venlafaxine Start 37.5 mg bid 375 mg 37 Nausea, dry mouth, headache,
(Effexor) (75100 mg bid) blood pressure elevation,
insomnia, nervousness,
XL form 225 mg (XL)
withdrawal syndrome
Start 37.5 mg qAM
wean slowly
75150 mg qAM
SNRIS
Atmoxetine 40 mg qAM 3 days then 100 mg 5.2 Nausea, dry mouth, headache,
(Strattera) 40 mg bid or 80 mg qAM blood pressure elevation,
(10, 18, 25, 40, 60, 80 mg tabs) insomnia, nervousness
OTHER MEDICATIONS
Selegiline (Eldepryl) 2040 mg 40 mg 914 Nausea, dizziness, confusion,
dry mouth
Sodium oxybate* Starting dose 2.25 mg qhs 9 g daily in divided 0.51 Nausea, headache, confusion,
(Xyrem) repeated in 2.54 hr (see text) doses enuresis, sleepwalking
*FDA approved for treatment of cataplexy.
FDA = U.S. Food and Drug Administration; NSRIs = nonselective serotonin reuptake inhibitors; SNRIs = selective norepinephrine reuptake inhibitors; SSRIs = selective
serotonin reuptake inhibitors.

of Hcrt1 (more stable that Hcrt2) increases alertness in

0 animals.101 Development of Hcrt analogues and/or an intra-
of cataplexy attacks per week
Median % change in number

nasal approach for administration are being evaluated.102

20 Placebo Histaminergic compounds are being developed.68 H3 recep-
tor antagonists bind the H3 receptor (an autoreceptor)
40
blocking the negative feedback of histamine and increasing
SXB 4.5 g overall histamine secretion. As mentioned previously, CSF
60
SXB 6.0 g histamine levels are low in narcolepsy and IH.37,38 As more
is learned about the pathophysiology of narcolepsy, improved
80
treatments will undoubtedly be available.
SXB 9.0 g
100
Baseline 4 weeks 8 weeks Narcolepsy in Children
FIGURE 248 Reduction in cataplexy attacks per week (% of baseline) in groups
treated with 4.5, 6.0, and 9.0 g of sodium oxybate (SXB). There was a significant
The onset of narcolepsy before age 4 is felt to be extremely
decrease even with the 4.5-g dose, and the improvement continued from 4 to 8 weeks. rare.1,103 EDS in children may manifest itself as a return to
Thus, the full benefit of sodium oxybate for treatment of cataplexy may require at least taking daytime naps in a child that previously discontinued
8 weeks (at least, at 9 g total dose). From Xyrem International Study Group: Further napping. In older children, daytime sleepiness may some-
evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double- times be manifested as symptoms similar to those of ADHD.
Symptoms of cataplexy may be difficult to elicit in children.
blind, placebo-controlled study in 228 patients. Sleep Med 2005;6:415421.
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468 Chapter 24 Hypersomnias of Central Origin
Cataplexy can be confused with syncope (except the child is
awake) or seizure-like activity. In children with narcolepsy,
cataplexy can sometimes be the first symptom and often the
first prominent symptom.104 If cataplexy is the first symptom,
an evaluation of narcolepsy due to medical condition (sec-
ondary narcolepsy) is indicated (including CNS imaging and
genetic testing). In one study, 43% of children had falls as
part of their attacks.104 During cataplexy, knees, head, and
jaw were the most often involved. Eyelids, arms, and trunk
were less often involved. More rarely, blurred vision, slurred
speech, or irregular breathing was noted. A cataplectic
facies was reported characterized by partially closed eyelids
and jaw weakness (open mouth). In some episodes of child-
hood cataplexy, a clear-cut emotional trigger may not be
noted. The development of obesity in children associated
with the onset of narcolepsy is common (up to 25%) and
nocturnal eating syndrome can be present. As discussed in
Chapter 14, children tend to have long sleep latencies on the
MSLT. For example, the mean sleep latency on the MSLT in
one study of normal prepubertal children was 19 16
minutes (in adults, 10.4 4.3).106 Therefore, use of sleep
latency criteria of 8 minutes or less may be problematic.
Some clinicians consider a mean sleep latency less than 12
minutes as consistent with daytime sleepiness in children.
Conversely, a study by Serra and colleagues104 found that
most of their children diagnosed with N+C had a mean sleep
latency of 5.3 minutes with a range of 1 to 13 minutes on the
MSLT. A repeat MSLT may be needed because lack of
SOREMPs does not rule out the diagnosis. A lumbar punc-
ture for CSF sampling (Hcrt1) could be considered if
possible/ambiguous cataplexy is present. The AASM Practice
Parameters for Treatment of Narcolepsy and Other Hyper-
somnias of Central Origin stated that methylphenidate or
modafinil in children 6 to 15 appears to be relatively safe in
the treatment of hypersomnias of central origin (Option).61
The practice parameters made no recommendation in this
age group regarding cataplexy. Fluoxetine, venlafaxine, and
SOXB have been used in children.104,105 A study of Israeli
children with narcolepsy reported successful use of modafinil
and SOXB for sleepiness.105
NARCOLEPSY DUE TO MEDICAL CONDITION
Narcolepsy Due to Medical Condition (NDMC) is a group
of disorders also known as secondary or symptomatic nar-
colepsy.1,107109 The patient must report or manifest daytime
sleepiness. The disorder must be associated with a medical
disorder known to cause narcolepsy and the combination of
either cataplexy or an MSLT meeting diagnostic criteria for
narcolepsy must be present. The ICSD-2 criteria for NDMC
are listed in Box 244. A low level of CSF Hcrt1 is also
acceptable evidence of NDMC.
Medical disorders commonly causing narcolepsy are
listed in Box 245. Note that if hypersomnia is thought sec-
ondary to one of the listed medical conditions but criteria
for narcolepsy are not met, the diagnosis is Hypersomnia
Due to Medical Condition (HDMC).
BOX 244
Narcolepsy Due to Medical Condition
A. Complaint of daytime sleepiness occurring almost daily
for at least 3 months.
B. One of the following is observed:
i. A definite history of cataplexy, defined as sudden
and transient episode of loss of muscle tone (muscle
weakness) triggered by emotion, is present.
ii. If cataplexy is not present or is very atypical,
PSG monitoring performed over the patients
habitual sleep period followed by an MSLT must
demonstrate a mean sleep latency on the MSLT of
<8 min with two or more SOREMPs despite sufficient
nocturnal sleep prior to the MSLT (minimum of
360 min).
iii. Hypocretin-1 levels in the CSF <110 pg/mL (or 30%
of the normal control values), provided the patient is
not comatose.
C. A significant underlying medical or neurologic disorder
accounts for the daytime sleepiness.
D. The hypersomnia is not better explained by another
sleep disorder, mental disorder, medications use, or
substance use disorder.
CSF = cerebrospinal fluid; MSLT = multiple sleep latency test;
PSG = polysomnography; SOREMPs = sleep-onset rapid eye movement
periods.
From American Academy of Sleep Medicine: International Classification
of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
BOX 245
Medical Disorders Causing Narcolepsy Due to
Medical Condition
NARCOLEPSY WITH CATAPLEXY
Tumors, sarcoidosis, arteriovenous malformations affecting
the hypothalamus
Multiple sclerosis plaques impairing the hypothalamus
Paraneoplastic syndrome anti-Ma2 antibodies
Neimann-Pick type C disease
Possibly Coffin-Lowry syndrome
NARCOLEPSY WITHOUT CATAPLEXY
Head trauma
Myotonic dystrophy
Prader-Willi syndrome (rarely with cataplexy)
Parkinsons disease
Multisystem atrophy
From American Academy of Sleep Medicine: International Classification of
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
DaneshGroup.com

Patients with idiopathic narcolepsy usually have a normal
neurologic examination and no definite pathology on brain
imaging. Patients with NDMC often have specific brain
pathology.107109 Damage to the hypothalamus due to sar-
coidosis, tumors,110 arteriovenous malformations, or cere-
brovascular accidents can cause NDMC. Other reported
associations of cerebral disease and narcolepsy include mul-
tiple sclerosis and Niemann-Pick disease type C.111 Daytime
sleepiness following closed head injury is a well-known syn-
drome.112 However, most patients with daytime sleepiness
following head trauma do not have narcolepsy. Postencepha-
litic narcolepsy was common in the 1920s, but no similar
epidemic has been recently described.
Disorders Associated with NDMC, Isolated
Cataplexy, or HDMC
Cataplexy can rarely occur with syndromes other than
idiopathic narcolepsy. In some cases, a diagnosis of NDMC
can be made. In others, it may be difficult to determine
whether daytime sleepiness is present (e.g., in the setting of
significant mental retardation). The term isolated cataplexy
implies the presence of cataplexy without daytime sleepiness.
Cataplexy has been reported in the Prader-Willi syndrome
(PWS),113116 Niemann-Pick disease type C,111,117,118 Coffin-
Lowry syndrome,119,120 Norries disease,121,122 and Moebius
syndrome.123 These patients have variable mental retarda-
tion and/or obvious neurologic deficits in contrast to the
patient with idiopathic narcolepsy.
Genetic Disorders Causing NDMC or Isolated Cataplexy
Prader-Willi Syndrome PWS is a genetic disorder usually asso-
ciated with a deletion of the long arm of chromosome 15 and
is characterized by hyperphagia, obesity, hypogonadotrophic
hypogonadism, behavioral disorders, and sleep disorders.113116
Abnormal growth hormone secretion results in short stature,
reduced muscle mass, and low bone density (scoliosis is
common). The characteristic appearance of PWS includes a
high narrow forehead, almond-shaped eyes, turned-down
lips, a prominent nasal bridge, and small hands and feet.
Intelligence is variable but usually ranges from low normal
to mild to moderately decreased. Patients with PWS may
have daytime sleepiness from a number of etiologies
including sleep apnea, narcolepsy, or the PWS itself. PWS
patients may manifest obstructive apnea, central apnea,
hypoventilation, or a mixture of these disorders. EDS is
reported commonly in persons with PWS, may begin early
in life, and has been correlated with daytime behavioral
issues. In fact, EDS has been reported independent of noc-
turnal sleep problems (sleep apnea), suggesting it is a primary
feature of PWS. Some sleepy persons with PWS meet the
diagnostic criteria for narcolepsy and PWS is considered a
cause of NDMC.1 Abnormal sleep architecture has been
reported in persons with PWS including reduced REM
latency and SOREMPs. These findings can be present in PWS
patients without significant sleep-related breathing prob-
lems. Although PWS is felt to most commonly cause NDMC
Chapter 24 Hypersomnias of Central Origin 469
without cataplexy, patients with PWS can have cataplexy114
(accurate history is often difficult to obtain in these patients).
Nevsimalova and associates115 found reduced levels of CSF
Hcrt1 levels in four patients with PWS. However, none had
cataplexy. Fronczek and coworkers116 found no difference in
the total number of Hcrt-containing neurons in seven PWS
patients compared with age-matched controls. If sleepiness
is present in PWS but criteria for narcolepsy are not met and
sleepiness is NOT felt to be due to sleep apnea, a diagnosis
of HDMC is appropriate.
Myotonic Dystrophy
Myotonic dystrophy type 1 (MD1) is an autosomal dominant
inherited disorder characterized by myotonia and muscle
weakness. The incidence is estimated to be about 1/10,000,
so it is a much more rare disorder than narcolepsy. Myotonia
is defined as repetitive muscle depolarization resulting in
muscle stiffness and impaired relaxation. The muscles
usually involved include facial, masseter, levator palpebra,
forearm, hand, pretibial, and sternocleidomastoid. Pharyn-
geal and laryngeal and muscles of respiration including the
diaphragm can be involved. Dysfunction of the hypotha-
lamic region can result in daytime sleepiness or daytime
sleepiness with SOREMPs (NDMC).1,107109,124 Involvement
of upper airway muscles can result in sleep apnea. Some
patients have abnormal ventilatory control and hypoventila-
tion. Involvement of the cardiac condition system can occur.
There are differences in presentation depending on the age
of onset. Congenital MD is apparent at birth and often
severe. Juvenile MD is characterized by symptoms that
appear between birth and adolescence. Adult-onset MD
usually appears in individuals aged 20 to 40 and tends to be
slowly progressive. Late-onset MD occurs after age 40 and
has mild symptoms.
Daytime sleepiness is a common complaint and can be
due to MD (hypersomnia due to medical condition), MD
as a cause of secondary narcolepsy (NDMC), or OSA.
Thus, several mechanisms can cause daytime sleepiness in
patients with MD.
On physical examination, findings include a narrow face,
premature frontal balding, distal weakness, and myotonia.
MD patients have decreased strength on hand grip but then
are slow to relax (distal myopathy with myotonia). There is
wasting of hand and forearm muscles. PSG can reveal OSA,
and PSG + MSLT can meet criteria for narcolepsy or simply
document EDS without SOREMPs.
The AASM Practice Parameter on the Treatment of Nar-
colepsy and Other Hypersomnias of Central Origin61 stated
methylphenidate and modafinil may be effective treatment
for MD (Optionthe lowest recommendation level) (see
Table 247). Two studies found modafinil to be effective,124,125
but a more recent small study did not show a benefit.126
Rare Genetic Disorders Causing NDMC
or Isolated Cataplexy
Niemann-Pick type C disease is a rare autosomal recessive
disorder characterized by lysosomal accumulation of
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470 Chapter 24 Hypersomnias of Central Origin
unesterfied cholesterol in many tissues as well as lysosomal
storage of sphingolipids in the brain and liver. Cataplexy may
be seen in up to 10% of children with Niemann-Pick type C
disease.111,117,118 The clinical manifestations and severity are
variable. Classic findings include hepatosplenomegaly, verti-
cal supranuclear gaze palsy, ataxia, dystonia, and dementia.
In one reported case, the CSF Hcrt was reduced but not into
the narcolepsy range.127
Coffin-Lowry syndrome is a rare X-linked disorder in
which affected males demonstrate severe mental retardation
with prominent dysmorphic features usually affecting the
face and hands. Typical facial features include a prominent
forehead, hypertelorism, a flat nasal bridge, downward-
sloping palpebral fissures, and a wide mouth with full lips.
Cataplexy has been described in these patients.119,120
Norries disease is a rare genetic condition that has also
been associated with cataplexy. It is an X-linked recessive
disorder causing ocular atrophy, mental retardation, deaf-
ness, and dysmorphic features.121,122 Defects in MAO genes
occur in some patients.122
Moebius syndrome consists of congenital paresis of the
seventh cranial nerve, orofacial and limb malformations, and
mental retardation. Cataplexy has been reported in children
with Moebius syndrome.123
IDIOPATHIC HYPERSOMNIA
IH is a poorly understood disorder of unknown etiology
characterized by unrefreshing sleep and difficulty awaken-
ing.1,4,53,128,129 In the past, IH was often classified into single
and multisymptom forms. However, the ICSD-2 has defined
two groups of patients with IH, those with and those without
a long sleep time. The diagnosis of IH remains a diagnosis of
exclusion of other disorders causing EDS (Box 246). There
is likely some overlap with patients with NC. Some patients
historically given a diagnosis of IH were later found to have
the upper airway resistance syndrome/mild OSA when more
sophisticated monitoring techniques such as esophageal
pressure monitoring were applied. Atypical depression
(hypersomnia instead of insomnia), the insufficient sleep
syndrome, medication side effects, narcolepsy (with delayed
cataplexy), and medical and neurologic disease must be
excluded. The MSLT criteria for IH include a mean sleep
latency less than 8 minutes with fewer than two SOREMPs.
In IH with long sleep time, an MSLT may not be practical.
IH with Long Sleep Time (IH+LST)
Manifestations Constant and severe daytime sleepiness is
reported with prolonged (3 hr) but unrefreshing naps and
a prolonged nocturnal sleep episode.1,128 There is great dif-
ficulty awakening in the morning or after naps. The major
sleep episode is greater than 10 hours (usually 1214 hr). SP
and HHs may be present (see Table 243). However, cata-
plexy is absent.
Autonomic Dysfunction Some patients with IH+LST report
symptoms including headaches (often migraine-like in
BOX 246
Idiopathic Hypersomnia with Long Sleep Time
Diagnostic Criteria
A. The patient has a complaint of excessive daytime
sleepiness occurring almost daily for at least 3 months.
B. The patient has prolonged nocturnal sleep time (>10 hr)
documented by interview, actigraphy, or sleep logs.
Waking up in the morning or at the end of naps is
laborious.
C. Nocturnal PSG has excluded other causes of daytime
sleepiness.
D. PSG demonstrates a short sleep latency and a major
sleep period that is prolonged to more than 10 hours in
duration.
E. If an MSLT is performed after the overnight PSG, a mean
sleep latency of less than 8 minutes and less than two
SOREMPs are demonstrated.
(Mean sleep latency in idiopathic hypersomnia with long
sleep time has been shown to be about 6.2 3.0 min.)
F. Hypersomnia is not better explained by another sleep
disorder, medical or neurologic disorder, medication, or
substance use disorder.
MSLT = multiple sleep latency test; PSG = polysomnography;
SOREMPs = sleep-onset rapid eye movement periods.
From American Academy of Sleep Medicine: International Classification of
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
nature), orthostatic hypotension with symptoms of periph-
eral vascular dysfunction (Raynauds phenomenonvascular
constriction on exposure to cold).
Prevalence Unknown; recent studies suggest that there is 1
IH patient for every 10 patients with narcolepsy.
Onset Usually before age 25.
Polysomnography Long sleep time with normal percentages
of the sleep stages. In some patients, the amount of stage N3
may be increased. The nocturnal REM latency is normal.
Twenty-four-hour PSG demonstrates greater than 10 hours
of sleep.
Multiple Sleep Latency Test It may be difficult to awaken a
patient to start the MSLT. If performed, an MSLT shows a
mean sleep latency (<8 min) and no or one SOREMP. For
MSLT to be reliable, it must follow PSG, the patient should
be withdrawn from medications affecting REM sleep for 15
days, and regular sleep should occur for at least 7 days before
testing. The mean sleep latency for IH was listed as 6.2 3.0
minutes in a recent review of the literature.55
CSF Hcrt CSF Hcrt1 levels are normal in patients with IH.25,26,59
A study also found low CSF histamine38 in patients with IH.
However, this finding was not specific for IH.
Diagnostic Approach CNS imaging is suggested if there is any
suspicion of a CNS lesion. The differential diagnosis includes
DaneshGroup.com

head trauma and sleepiness associated with a psychiatric
disorder or structural CNS lesion. A sleep diary or clinical
history should eliminate the possibility of the insufficient
sleep syndrome.
Treatment Amphetamines, methylphenidate, and moda-
finil61,128,130 have all been used with variable success for treat-
ment of daytime sleepiness (see Table 247). The AASM
Practice Parameters for Treatment of Narcolepsy and Other
Hypersomnias of Central Origin state that modafinil may
be effective for treatment of idiopathic hypersomnia
(Option).61 Amphetamine, methamphetamine, and methyl-
phenidate were also listed as treatments for IH (Option).
IH without Long Sleep Time (IHLST)
IH without long sleep time (IHLST) patients have similar
symptoms as IH+LST except that the nocturnal sleep time
is between 6 and 10 hours. The ICSD-2 criteria are listed in
Box 247. The disorder has also been called idiopathic CNS
hypersomnia. Comparison of patients with narcolepsy and
IH are also illustrated in Table 243.
Manifestations Constant and severe daytime sleepiness is
reported with unrefreshing naps and a normal to slightly
prolonged nocturnal sleep episode (610 hr). Patients may
report difficulty awakening in the morning or after naps. SP
and HHs may be present. However, cataplexy is absent.
Autonomic Dysfunction Some patients with IHLST report
symptoms including headaches (often migraine in nature),
orthostatic hypotension with symptoms of peripheral vascu-
lar dysfunction (Raynauds phenomenonvascular con-
striction on exposure to cold).
BOX 247
Idiopathic Hypersomnia without Long Sleep
TimeDiagnostic Criteria
A. The patient has a complaint of excessive daytime
sleepiness occurring almost daily for at least 3 months.
B. The patient has normal nocturnal sleep (>6 hr but
<10 hr), documented by interview, actigraphy, or sleep
logs.
C. Nocturnal PSG has excluded other causes of daytime
sleepiness.
D. PSG demonstrates a major sleep period that is normal in
duration.
E. An MSLT following the overnight PSG demonstrates a
mean sleep latency of less than 8 minutes with fewer
than two SOREMPs.
(MSL in idiopathic hypersomnia has been shown to be
6.2 + 3.0 min).
F. Hypersomnia is not better explained by another sleep
disorder, medical or neurological disorder, medication,
or substance use disorder.
MSL = mean sleep latency; MSLT = multiple sleep latency test; PSG =
polysomnography; SOREMPs = sleep-onset rapid eye movement periods.
Chapter 24 Hypersomnias of Central Origin 471
Prevalence Unknown; recent studies suggest that there is 1
IH patient for every 10 patients with narcolepsy. Males and
females are equally affected.
Onset Usually before age 25.
Polysomnography Total sleep time greater than 6 hours but
less than 10 hours. Normal distribution of the sleep stages.
The sleep efficiency is greater than 85%. The nocturnal REM
latency is normal.
Multiple Sleep Latency Test Mean sleep latency (<8 min) and
no or one SOREMP.
CSF Hcrt1 Levels CSF Hcrt1 levels are normal in IH patients.
One study found CSF histamine to be low.38
Diagnostic Approach CNS imaging is suggested if there is any
suspicion of a CNS lesion. Psychiatric consultation may also
be considered. The differential diagnosis includes head
trauma and sleepiness associated with a psychiatric disorder
or structural CNS lesion, the chronic fatigue syndrome,
behaviorally induced insufficient sleep, and NC. The PSG
should rule out sleep apnea. A sleep diary or clinical history
should eliminate the possibility of the insufficient sleep
syndrome.
Treatment Same as for IH+LST.
Recurrent Hypersomnia (Including Kleine-Levin
Syndrome and Menstrual-Related Hypersomnia)
Kleine-Levin Syndrome
Recurrent episodes of hypersomnia are noted and are clearly
associated with behavioral abnormalities.1,131 These may
include binge eating, hypersexuality, abnormal behaviors
that exhibit irritability and aggression as well as cognitive
abnormalities such as a feel of unreality, confusion, and hal-
lucinations (Box 248). Episodes occur 1 to 10 times per year
and last a few days to several weeks. Kleine-Levin syndrome
(KLS) is rare with just over 200 cases reported. The
BOX 248
Recurrent Hypersomnia (Including Kleine-Levin
Syndrome and Menstrual-Related Hypersomnia)
A. The patient experiences recurrent episodes of excessive
sleepiness of 2 days to 4 weeks in duration.
B. Episodes recur at least once a year.
C. The patient has normal alertness, cognitive function,
and behavior between attacks.
D. Hypersomnia is not better explained by another sleep
disorder, medical or neurologic disorder, medication, or
substance use disorder.
From American Academy of Sleep Medicine: International Classification of
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
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472 Chapter 24 Hypersomnias of Central Origin
male-to-female ratio is 4/1. In some studies, the frequency
of HLA DQB1*602 was increased. Precipitating events
including a flulike illness, upper respiratory infection, head
trauma, or exposure to anesthesia have been reported. The
second decade (adolescence) is the usual time of onset. The
disease course usually lasts 1 to several years. Because of
the limited number of patients, no large well-controlled
study exists. Improvement has been reported with lithium,
amantadine, lamotrigine, and valproic acid.3 The AASM
Standard of Practice Paper on Treatment of Narcolepsy and
Other Hypersomnias of Central Origin listed lithium as
possibly effective.61 Lithium may reduce the duration of
episodes and reduce the undesirable behaviors. Methylphe-
nidate and modafinil could be used for daytime sleepiness.
Menstrual Syndrome
Recurrent episodes of sleepiness associated with the men-
strual cycle. The syndrome occurs within the first few months
of menarche. Episodes usually last 1 week with resolution at
the time of menses. Hormone imbalance is a likely explana-
tion because oral contraceptives result in a prolonged
remission.
Other
Recurrent hypersomnia without behavioral abnormalities.
Behaviorally Induced Insufficient Sleep Syndrome
These patients fail to obtain sufficient nocturnal sleep to
maintain daytime alertness and mental functioning. The
diagnosis depends on patient report or sleep logs but can
also be documented by actigraphy. Patients characteristically
sleep longer on weekends and vacations. They usually report
feeling more refreshed with a longer sleep period. The
ICSD-2 criteria for behaviorally induced insufficient sleep
syndrome are listed in Box 249.
A sleep study is not needed for diagnosis but, if per-
formed owing to suspicion of other disorders, will often
show a short sleep latency and high sleep efficiency. There is
sometimes evidence of stage N3 or stage R rebound (high
amount of those sleep stages).132 Note that up to 30% of
normal populations have a mean sleep latency less than 8
minutes. The complaint of daytime sleepiness and documen-
tation of inadequate sleep are more important than the
MSLT finding.
Hypersomnia Due to Medical Condition
In these patients, hypersomnia is due to a medical condition
or neurologic disorder. The patients do not meet criteria for
narcolepsy due to medical disorderotherwise that diagno-
sis would be made. The ICSD-2 criteria for hypersomnia due
to medical condition are listed in Box 2410. Disorders com-
monly associated with hypersomnia due to medical condi-
tion are listed in Box 2411. Some of these disorders were
discussed in previous sections. Note that up to 30% of normal
populations have a mean sleep latency less than 8 minutes. A
diagnosis of hypersomnia due to medical condition assumes
that there is a complaint of daytime sleepiness and that this
is not simply the result of a decreased amount of sleep.
BOX 249
Behaviorally Induced Insufficient Sleep
SyndromeDiagnostic Criteria
A. The patient has a complaint of excessive sleepiness, or
in prepubertal children, a complaint of behavior
abnormality suggesting sleepiness. The abnormal sleep
pattern is present almost daily for at least 3 months.
B. The patients habitual sleep episode, established using
history, sleep log, or actigraphy is usually shorter than
expected for age-adjusted normative data.
C. When the habitual sleep schedule in not maintained
(weekends or vacation time), patients will sleep
considerably longer than usual.
D. If diagnostic PSG is performed (not required for
diagnosis), sleep latency is less than 10 minutes and
sleep efficiency greater than 90%. During the MSLT, a
short sleep latency less than 10 minutes (with or without
multiple SOREMPs) may be observed.
E. The hypersomnia is not better explained by another
sleep disorder, medical or neurologic disorder,
medication, or substance use disorder.
MSLT = multiple sleep latency test; PSG = polysomnography;
SOREMPs = sleep-onset rapid eye movement periods.
From American Academy of Sleep Medicine: International Classification of
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
BOX 2410
Hypersomnia Due to Medical Condition
Diagnostic Criteria
A. The patient has a complaint of excessive daytime
sleepiness occurring almost daily for at least 3 months.
B. A significant underlying medical or neurologic disorder
accounts for the daytime sleepiness.
C. If an MSLT is performed, the mean sleep latency is less
than 8 minutes with no more than one SOREMP after
PSG performed during the patients habitual sleep
period, with a minimum total sleep time of 6 hours.
D. The hypersomnia is not better explained by another
sleep disorder, medical or neurologic disorder,
medication, or substance use disorder.
MSLT = multiple sleep latency test; PSG = polysomnography;
SOREMP = sleep-onset rapid eye movement period.
From American Academy of Sleep Medicine: International Classification of
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
Head Trauma Head trauma can be associated with EDS and
less commonly a cause of secondary narcolepsy. Part of the
hypersomnia could be due to injury to the Hcrt neurons or
other wake-promoting systems. Hcrt levels can be reduced
after severe head injury. However, true narcolepsy due to
head trauma is rare.
Parkinsons Disease Patients with Parkinsons disease may
exhibit daytime sleepiness due to medications (sleep attacks
with DA agonists in some patients), OSA, and possibly the
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 Chapter 24 Hypersomnias of Central Origin 473

BOX 2411 BOX 2412

Disorders Associated with Hypersomnia Due to
Medical Condition
A. Posttraumatic hypersomnia.
B. Hypersomnia due to Parkinsons disease.
C. Genetic disorders associated with central hypersomnia
Niemann-Pick type C, myotonic dystrophy, Norries
disease, Prader-Willi syndrome, Moebius syndrome
D. Genetic disorders associated with central hypersomnia
and SRBDs
Prader-Willi, myotonic dystrophy
E. Hypersomnia due to endocrine disorder
(hypothyroidism)
F. Hypersomnia due to central nervous system lesion
(infection, tumor)
G. Hypersomnia due to toxic metabolic syndrome
SRBDs = sleep-related breathing disorders.
From American Academy of Sleep Medicine: International Classification of
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
Hypersomnia Due to Drug or Substance
HYPERSOMNIA DUE TO DRUG OR SUBSTANCE (ABUSE)
A. The patient has a complaint of sleepiness or excessive
sleep.
B. The complaint is believed secondary to current use,
recent discontinuation, or prior prolonged use of drugs.
C. The hypersomnia is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, or medication use.
HYPERSOMNIA DUE TO DRUG OR
SUBSTANCE (MEDICATIONS)
A. The patient has a complaint of sleepiness or excessive
sleep.
B. The complaint is believed secondary to current use,
recent discontinuation, or prior prolonged use of a
prescribed medication.
C. The hypersomnia is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, or substance use disorder.

disease itself.133 The RBD is very common and may precede BOX 2413
Parkinsons disease onset. The Hcrt levels in the CSF are
Common Medications Associated with
normal but reduced in the lateral ventricles. Recently, one
Daytime Sleepiness
study found a reduction in Hcrt cells in the hypothalamus of
patients with Parkinsons disease.134 Benzodiazepines
Hypnotics (especially with long half-life)
Treatment of Hypersomnia Due to Medical Condition The AASM Dopamine agonists
Practice Parameters for Treatment of Narcolepsy and Hyper- Antidepressants
somnia of Central Origin (see Table 247) stated that Sedating (usually > frequent sedation [trazodone,
modafinil may be effective for treatment of excessive daytime doxepin, mirtazapine])
sleepiness in Parkinsons disease (Option), MD (Option), Nonsedating (usually <15%)lower percentage
and multiple sclerosis (Guideline).62 It was also stated that associated with sedationincluding citalopram,
fluoxetine, paroxetine, sertraline
methylphenidate may be indicated for treatment of EDS due
Narcotics
to MD (Option). If modafinil is not effective in Parkinsons
Antihypertensives: Clonidine, methyldopa
disease or multiple sclerosis, treatment with methylpheni-
Antihistamines (first generation)
date could also be tried.
Antiepileptics
Dilantin, carbamazepine, phenobarbital, lamotrigine,
Hypersomnia Due to Drug or Substance gabapentin, valproic acid, topiramate
This diagnosis is reserved for patients with excessive sleep or
daytime sleepiness believed to be due to substance use (Box
2412). There is often a historical report of symptoms begin- insufficient sleep syndrome, or chronic fatigue. Medications
ning with the starting of a particular medication. A sleep can also result in worsening of symptoms of another sleep
study is not needed unless there is the suspicion of another disorder.
sleep disorder. An MSLT may be needed if narcolepsy is
suspected. A urine drug screen may help make the diagnosis Hypersomnia Not Due to Substance or Known
of substance abuse. The diagnosis is confirmed when symp-
Physiologic Condition
toms improve after discontinuation of the substance. A list
of common medications associated with daytime sleepi- Nonorganic HypersomniaHypersomnia Associated
ness135 is listed in Box 2413. One must also remember that with Mental Disorders
medications causing insomnia can indirectly result in The name of this category is somewhat confusing but most
daytime sleepiness. disorders of daytime sleepiness classified here are associated
The differential diagnosis of hypersomnia due to drug or with mental disorders (Box 2414). Women are more
medication includes sleep apnea, behaviorally induced commonly affected than men. Sleep is often said to be
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474 Chapter 24 Hypersomnias of Central Origin
BOX 2414
Hypersomnia Not Due to Substance or Known
Physiologic Condition: Nonorganic
HypersomniaHypersomnia Associated
with Mental Disorders: Diagnostic Criteria
and Pathologic Subtypes
DIAGNOSTIC CRITERIA
A. The patient has a complaint of excessive daytime
sleepiness or excessive sleep.
B. The complaint is temporally associated with a
psychiatric diagnosis.
C. Polysomnography monitoring demonstrates both of the
following:
i. Reduced sleep efficiency and increased frequency
and duration of awakenings.
ii. Variable, often normal, mean sleep latencies on the
MSLT.
D. The hypersomnia is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, or substance use disorder.
PATHOLOGIC SUBTYPES
1. Hypersomnia associated with a major depressive
episode.
2. Hypersomnia as a conversion disorder or an
undifferentiated somatoform disorder.
3. Hypersomnia associated with seasonal affective disorder.
MSLT = multiple sleep latency test.
From American Academy of Sleep Medicine: International Classification of
Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. Westchester, IL:
American Academy of Sleep Medicine, 2005.
nonrestorative. The disorder class represents 5% to 7% of
patients seen with complaints of EDS.1,136
Hypersomnia Associated with a Major Depressive Episode Depres-
sion is more often associated with complaints of insomnia.
However, hypersomnia is frequently associated with atypical
depression (mood reactivityability to improve with posi-
tive events, overeating) and bipolar type II disorder (major
recurrent depression episodes with hypomania episodes).
Long hours are spent in bed. However, the sleep latency on
MSLT is usually normal.137
Hypersomnia Associated with Seasonal Affective Disorder Daytime
fatigue, loss of concentration, increased appetite for carbo-
hydrates, and weight gain have been reported with seasonal
affective disorder (SAD).
Hypersomnia as a Conversion Disorder or an Undifferentiated
Somatoform Disorder Pseudocataplexy and pseudonarcolepsy
have been reported.
Physiologic (Organic Hypersomnia), Unspecified
Daily sleepiness for at least 3 months with an MSLT showing
sleep latency less than 8 minutes and fewer than two
SOREMPs that do not meet criteria for other disorders are
classified here.
CLINICAL REVIEW QUESTIONS
1. A patient is being evaluated for severe daytime sleepi-
ness (Epworth Sleepiness Scale 20/24). He reports sleep-
ing about 7 hours per night. The patient reports neck
muscle weakness (head nods) when he hears or tells a
joke. He undergoes a PSG followed by an MSLT. The
PSG is fairly normal without evidence of sleep apnea.
On the MSLT, the mean sleep latency is 4 minutes but
only one of five naps has REM sleep. What is the
diagnosis?
A. Narcolepsy without cataplexy.
B. Idiopathic hypersomnia with long sleep time.
C. Idiopathic hypersomnia without long sleep time.
D. Narcolepsy with cataplexy.
2. Which of the following is an effective (and FDA-
approved) treatment for both daytime sleepiness and
cataplexy?
A. Sodium oxybate (SOXB).
B. Fluoxetine.
C. Modafinil.
D. Methylphenidate.
3. A patient with daytime sleepiness denies cataplexy. He
normally sleeps about 8 hours per night. The nocturnal
PSG shows a sleep latency of 5 minutes and a REM
latency of 10 minutes. The total sleep time is normal and
there is no evidence of sleep apnea, but the periodic limb
movement index is 20/hr. The MSLT shows a mean sleep
latency of 3 minutes and REM sleep on one of five naps.
What is the likely diagnosis?
A. Narcolepsy without cataplexy.
B. Idiopathic hypersomnia with long sleep time.
C. Idiopathic hypersomnia without long sleep time.
D. PLMD.
4. CSF Hcrt1 is low or undetectable in what percentage of
patients with N+C?
A. 100%.
B. 9095%.
C. 85%.
D. 70%.
5. A 20-year-old male with N+C is being treated with
modafinil 400 mg daily. Daytime sleepiness has improved
but is still a problem from 4 to 7 PM. Which of the fol-
lowing would NOT be a reasonable intervention?
A. Change to modafinil 200 mg qAM, 200 mg in early
afternoon.
B. Change to modafinil 300 mg qAM, 100 mg in early
afternoon.
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C. Change to armodafinil 250 mg qAM.
D. Change to methylphenidate 2030 mg in the AM.
6. An 18-year-old man is evaluated for three episodes of
daytime sleepiness each lasting about 6 weeks that have
occurred over the last 8 months. The patient does not
have periods of depression. Which of the following is
NOT true about the patients disorder?
A. Lithium has been reported to be effective is small
case series (delay or preventing recurrences).
B. Hypersexuality can occur during the periods of
excessive sleepiness.
C. Reports of derealization and cognitive impairment
are common.
D. Increased amount of daily sleepusually 15 hours
or greater.
E. No precipitating event is usually reported.
7. A 40-year-old patient with narcolepsy has disabling
daytime sleepiness despite taking modafinil 400 mg
daily (Epworth Sleepiness Score 16/24). Cataplexy is not
reported. What is the first intervention that you
recommend?
A. Increase modafinil to 600 mg daily.
B. Change to methylphenidate 20 mg bid.
C. Begin SOXB.
D. Schedule naps.
8. What duration of nocturnal sleep separates patients
with IH+LST from those with IHLST?
A. Sleep duration >8 hr.
B. Sleep duration >10 hr.
C. Sleep duration >12 hr.
D. Sleep duration >14 hr.
9. Which of the following is NOT true about cataplexy?
A. The duration of cataplexy is seconds to several
minutes.
B. Laughter or hearing or telling a joke is the most
common precipitating event.
C. Consciousness is preserved during episodes of
cataplexy.
D. Histamine activity in the tuberomammillary region
is lower in cataplexy than in REM sleep.
E. Deep tendon reflexes are absent during an attack of
cataplexy.
10. What is the MSLT criterion for diagnosis of
narcolepsy?
A. Sleep latency <8 min and two or more SOREMPs.
B. Sleep latency 8 min and two or more SOREMPs.
C. Sleep latency <5 min and two or more SOREMPs.
D. Sleep latency 5 min and two or more SOREMPs.
Chapter 24 Hypersomnias of Central Origin 475
11. A patient with Prader-Willi syndrome (PWS) is being
evaluated with daytime sleepiness. He denies cataplexy.
A PSG shows an AHI of 3/hr. An MSLT shows a sleep
latency of 3 minutes and one SOREMP. Which of the
following is the most likely diagnosis?
A. Narcolepsy Due to Medical Condition (NDMC).
B. OSA.
C. Hypersomnia Due to Medical Condition.
D. Idiopathic hypersomnia without long sleep time.
12. If one member of a pair of identical twins has narco-
lepsy, in what percentage of twin pairs is the other twin
likely to have or develop narcolepsy?
A. 10%.
B. 30%.
C. 50%.
D. 75%.
13. A patient is diagnosed with narcolepsy. What percent-
age of his first-degree relatives are likely to have or
develop narcolepsy?
A. 12%.
B. 5%.
C. 10%.
D. 25%.
14. Which of the following is NOT true about modafinil?
A. Headache is the most common side effect.
B. Modafinil can alter the metabolism of oral
contraceptives.
C. If modafinil is given in the morning, it can still
disturb nocturnal sleep
D. Modafinil is very rarely associated with a life-
threatening rash.
Answers
1. D. The patient reports cataplexy and daytime sleepi-
ness. In this patient, an MSLT is confirmatory but is not
essential for the diagnosis of N+C. Only about 70% of
patients with N+C will have an MSLT meeting diagnos-
tic criteria on a given day.
2. A. SOXB is effective for the treatment of both daytime
sleepiness and cataplexy. Methylphenidate may have a
modest anticataplectic effect, but modafinil has no effect
on cataplexy. Fluoxetine does not treat daytime
sleepiness.
3. A. The ICSD-2 diagnostic criteria did not mention the
nocturnal REM latency. However, a study by Aldrich
and coworkers53 found that a short nocturnal REM
latency had a high specificity for the diagnosis of narco-
lepsy as well as a moderately high positive predictive
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476 Chapter 24 Hypersomnias of Central Origin
value. PLMS is common in patients with narcolepsy (see
Chapter 23).
4. B. About 9095% of patients with N+C have a low or
undetectable CSF Hcrt1. However, 510% of patients
with N+C do not have a reduced CSF Hcrt.
5. D. Patients taking modafinil in the morning sometimes
have problems with alertness in the late afternoon and
early evening. Answers A and B are interventions that
might be effective. One might start with A and change
to B if reduction in the am modafinil caused worsening
of morning sleepiness. Answer C is also reasonable
because armodafinil has a longer duration of action and
may be more effective than modafinil given as a morning
dose. Answer D is unlikely to be effective given the short
duration of action of methylphenidate. Sustained-release
formulations of methylphenidate might be more useful.
6. E. The Kleine-Levin syndrome is characterized by
repetitive periods of hypersomnia often associated with
hyperphagia and hypersexuality. Over 80% of patients
remember an event associated with onset of symptoms.
A precipitating event is often identified and has included
infection (coldlike symptoms with fever), sleep depriva-
tion, alcohol use, and head trauma.
7. B. Modafinil is convenient but not necessarily as effec-
tive as stimulant medications. The daytime sleepiness of
patients with narcolepsy may respond better to methyl-
phenidate than to modafinil. Although SOXB is also a
reasonable option, the patient does not have cataplexy
and SOXB is much more expensive than most stimulant
medications. Some patients may respond to higher
doses of modafinil than 600 mg, but this patient has
received little benefit from the medication. Scheduled
naps may be helpful but would not be considered as the
major therapeutic intervention.
8. B. Patients with IH+LST have a nocturnal sleep period
>10 hr.
9. D. Cataplexy is associated with much higher histamine
activity in the tuberomammillary area of the ventrolat-
eral hypothalamus during cataplexy than during REM
sleep. This is believed to be one of the reasons patients
remain conscious during cataplexy.
10. B. The MSLT criterion for diagnosis of narcolepsy is a
sleep latency 8 min and two or more SOREMPs.
11. C. PWS can be associated with daytime sleepiness not
due to sleep apnea or narcolepsy. The patient does not
have cataplexy and does not meet MSLT criteria for
narcolepsy. The OSA is too mild to explain the signifi-
cant daytime sleepiness. The best answer in the case is
Hypersomnia Due to a Medical Disorder. If criteria for
narcolepsy were present, B would be the correct answer.
12. B. 30% of twin pairs are concordant for narcolepsy.
13. A. 12% of the first-degree relatives are at risk for
narcolepsy.
14. C. Modafinil does not disturb nocturnal sleep if given
in the morning. Women of reproductive age should
always be informed that the effectiveness of oral contra-
ceptives may be impaired by modafinil.
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80. Darwish M, Kirby M, DAndrea DM, et al: Pharmacokinetics
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82. Mignot E, Nishino S, Guilleminault C, et al: Modafinil binds
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84. Ferraro L, Tanganellis S, OConnor WT, et al: The vigilance
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85. Gallopin T, Luppi PH, Rambert FA, et al: Effect of wake-
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86. Gerrard P, Malcolm R: Mechanisms of modafinil: a review of
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88. U.S. Xyrem Multicenter Study Group: A randomized, double-
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89. U.S. Xyrem Multicenter Study Group: A 12-month open-label,
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oxybate for the treatment of narcolepsy. Sleep 2003;1:3135.
90. The Xyrem International Study Group: A double-blind,
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91. Black J, Houghton WC: Sodium oxybate improves excessive
daytime sleepiness in narcolepsy. Sleep 2006;29:939946.
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onstrates long-term efficacy for the treatment of cataplexy in
patients with narcolepsy. Sleep Med 2004;5:119123.
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94. Black J, Pardi D, Hornfledt CS, Inhaber N: The nightly admin-
istration of sodium oxybate results in significant reduction in
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95. George CFP, Feldman N, Inaber N, et al: A safety trial of
sodium oxybate in patients with obstructive sleep apnea. Sleep
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96. Mayer G, Ewert-Meier K, Hephata K: Selegeline hydroch-
loride treatment in narcolepsy: a double-blind, placebo-
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97. Nishino S, Mignot E: Pharmacological aspects of human and
canine narcolepsy. Prog Neurobiol 1997;52:2778.
98. Frey J, Darbonne C: Fluoxetine suppresses human cataplexy.
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99. Aldrich M, Rogers AE: Exacerbation of human cataplexy by
prazosin. Sleep 1989;12:254256.
100. Valko PO, Khatami R, Baumann CR, Bassetti CL: No persis-
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109. Nishino S, Kanbayashi T: Symptomatic narcolepsy, cataplexy,
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110. Aldrich MS, Naylor MW: Narcolepsy associated with lesions
of the diencephalon. Neurology 1989;39:15051508.
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112. Guilleminault C, Van den Hoed J, Miles L: Posttraumatic
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114. Tobias ES, Tolmie GJ, Stephenson JBP: Cataplexy in Prader-
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deficiency in Prader-Willi syndrome. Eur J Neurol 2005;12:
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116. Fronczek R, Lammers GJ, Balesar R, et al: The number of
hypothalamic hypocretin orexin neurons is not affected in
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118. Vanier MT, Suzuki K: Recent advances in elucidating
Niemann-Pick C disease. Brain Pathol 1998;8:163174.
119. Nelson GB, Hahn JS: Stimulus-induced drop episodes in
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with Coffin-Lowry syndrome and cataplexy. Genet Couns
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121. Vossler DG, Wyler AR, Wilkus RJ, et al: Cataplexy and mono-
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122. Chen ZY, Denney RM, Breakfield XO: Norrie disease and
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daytime sleepiness by modafinil in patients with myotonic
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125. MacDonald JR, Hill JD, Tarnopolsky MA: Modafinil reduces
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126. Orlikowski D, Chevret S, Quera-Salva MA, et al: Modafinil for
the treatment of hypersomnia associated with myotonic mus-
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ized, double-blind, placebo-controlled, 4-week trial. Clin Ther
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128. Bassetti C, Aldrich MS: Idiopathic hypersomnia. Brain
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129. Anderson KN, Pilsworth S, Sharples LD, et al: Idiopathic
hypersomnia: a study of 77 cases. Sleep 2007;30:12741281.
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134. Fronczek R, Overeem S, Lee SY, et al: Hypocretin loss in
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136. Plante DT, Winkleman JW: Sleep disturbance in bipolar dis-
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using the multiple sleep latency test. Am J Psychiatry 1991;
148:11771181.
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 Chapter 25

Insomnia

Chapter Points the insomnia is causing marked distress or is an

A diagnosis of insomnia requires some type of
daytime impairment related to nocturnal sleep
difficulty.
Adjustment insomnia is characterized by insomnia
with a duration less than 3 months that is temporally
associated with an identifiable stressor and expected
to resolve.
Psychophysiologic insomnia must have a duration
of at least 1 month and is characterized by
conditioned sleep-preventing associationsthe
bedroom is a stimulus for wake not sleep. Patients can
often fall asleep better in a novel setting or at home
outside the bedroom.
Idiopathic insomnia is present since infancy or
childhood, has no identifiable precipitant (insidious
onset), and no period of sustained remission.
Paradoxical insomnia is characterized by a duration
of at least 1 month and complaints of little or no
sleep but relatively minor daytime consequences and
no or rare naps. The degree of sleep reduction
reported far exceeds that noted with objective
determinations of sleep (PSG) or estimates of sleep
(actigraphy).
Inadequate sleep hygiene is characterized by a
duration of at least 1 month and improper sleep
scheduling, stimulating activities near bedtime, or use
of the bed for nonsleep activities.
Insomnia Due to Drug or Substance is characterized
by a duration of at least 1 month and ongoing TECHNIQUE EVIDENCE
dependence and abuse of sleep-disruptive medication
or substance with symptoms either during intoxication Stimulus
or withdrawal OR current exposure to medication or
substance known to disturb sleep in susceptible
individuals. The complaint should be temporally
associated with use or withdrawal of the medication or
substance.
Sleep
Insomnia Due to Mental Disorder is characterized by
insomnia of a duration of at least 1 month that is
temporally associated with (or slightly preceding) the
onset of the mental disorder, waxes and wanes with Relaxation
the severity of the mental disorder, and is more
prominent than expected for the disorder such that
independent focus of treatment.
Behavioral Insomnia of Childhood is divided into
sleep-association type (requires certain conditions for
sleep onset) and limit-setting type (refusal to go to
sleep).
The most common cause of insomnia is the presence
of a psychiatric disorder.
The most important characteristic of a BZRA to
consider when choosing a medication to treat
insomnia is the duration of action.
Hypnotics with a short duration of action are indicated
to treat sleep-onset insomnia (e.g., zaleplon, ramelteon).
BZRAs with intermediate duration of action are
indicated to treat sleep-onset or sleep-maintenance
insomnia (zolpidem CR, eszopiclone, temazepam).
Zolpidem is also effective for sleep-maintenance
insomnia in some patients.
CBT of insomnia (also known as CBTI) is effective for
both primary and secondary (co-morbid) insomnia
including insomnia due to medical conditions. The
combination of a hypnotic and CBTI is NOT more
effective than CBTI alone for primary insomnia.
CBTI is defined as cognitive therapy + stimulus control
and/or sleep restriction with or without relaxation
therapy.
Major behavioral techniques with their level of
evidence are shown in the following table.
BRIEF SUMMARY
Standard If not sleepy, get out
control of bed until sleepy.
Have the same wake
time every day.
Use the bed only for
sleep.
Standard Restrict time in bed so
restriction sleep 85% of time
in bed.
Guideline Progressive muscle
relaxation.
Guided imagery.

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482 Chapter 25 Insomnia
TECHNIQUE EVIDENCE BRIEF SUMMARY
Biofeedback Guideline Reduce somatic
tension.
Paradoxical Guideline Passively remain
intention awake and avoid
any effort (intention)
to fall asleep.
Sleep No Improved sleep
hygiene recommendation scheduling, used
education bed only for sleep.
Options for treatment of insomnia in a patient with
depression include using (1) a sedating antidepressant
at a dose effective for depression, (2) an effective
antidepressant + a low dose of a sedating
antidepressant, (3) an effective antidepressant + a
BZRA. In patients with a history of alcohol or drug
dependence, use of a BZRA should be avoided.
In patients with benign prostatic hypertrophy,
medications with anticholinergic side effects should
be avoided.
The International Classification of Sleep Disorders, second
edition (ICSD-2)1 lists diagnostic criteria for insomnia (Box
251) that include requirements for an insomnia sleep com-
plaint, adequate opportunity/sleep, and some form of
daytime impairment related to the sleep difficulty. The sleep
complaints associated with insomnia include difficulty initi-
ating sleep (sleep-onset insomnia), difficulty maintaining
sleep (sleep-maintenance insomnia), waking up too early,
or sleep that is chronically nonrestorative or poor in quality.
A diagnosis of insomnia requires that patients must report
at least one of these insomnia complaints. However, it is not
uncommon for individual patients to report all of them.
There must be adequate opportunity and circumstances for
sleep to occur. A diagnosis of insomnia also requires evi-
dence of daytime impairment related to the sleep problem.
Patients suffering from insomnia may report a wide variety
of complaints (see Box 251) including fatigue or malaise,
problems with attention or concentration, memory impair-
ment, social or vocational dysfunction, and poor school per-
formance. Other symptoms associated with insomnia include
mood disturbance or irritability; daytime sleepiness; reduc-
tion in motivation or initiative; proneness to error/accidents
at work or while driving; tension headaches or gastrointesti-
nal symptoms in response to sleep loss; and concerns or
worries about sleep.1 In children, the sleep difficulty is often
reported by the caretaker and may consist of observed
bedtime resistance or inability to sleep independently.
Although the minimum duration of insomnia complaints is
not specified in the definition of insomnia (see Box 251),
the diagnostic criteria for several individual insomnia types
does specify a minimum duration of 1 month.1
BOX 251
Diagnostic Criteria for Insomnia
A. A complaint of difficulty initiating sleep, difficulty
maintaining sleep, or waking up too early, or sleep that
is chronically nonrestorative or of poor quality. In
children, the sleep difficulty is often reported by the
caretaker and may consist of observed bedtime
resistance or inability to sleep independently.
B. The above sleep difficulty occurs despite adequate
opportunity and circumstances for sleep.
C. At least one of the following forms of daytime
impairment related to the night sleep difficulty is
reported by the patient.
i. Fatigue or malaise.
ii. Attention, concentration, or memory impairment.
iii. Social or vocational dysfunction or poor school
performance.
iv. Mood disturbance or irritability.
v. Daytime sleepiness.
vi. Motivation, energy, or initiative reduction.
vii. Proneness to error/accidents at work or while
driving.
viii. Tension, headaches, or gastrointestinal symptoms in
response to sleep loss.
ix. Concerns or worries about sleep.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
PREVALENCE OF INSOMNIA AND RISK FACTORS
It has been estimated that insomnia complaints occur on at
least a few nights per year in 33% to 50% of the adult popula-
tion. Insomnia complaints plus symptoms of impairment
due to insomnia occur in 10% to 15% of the population.
Specific insomnia disorders occur in 5% to 10%.25 A number
of risk factors for the development of insomnia have been
identified, including older age, female gender, co-morbid
problems (depression and other psychiatric disorders, sub-
stance abuse), shift work, unemployment, and lower socio-
economic status. Some studies suggest that single, divorced,
and separated patients have greater insomnia rates than
married patients. The most common cause of insomnia in
patients evaluated by a physician is insomnia due to or asso-
ciated with depression. Insomnia occurs in the majority of
patients (80%) with major depressive or chronic pain disor-
ders. Persistent insomnia symptoms increase the likeli-
hood of developing a major depression within a 1-year
period by a factor of four.3 In addition, up to one third of
all cases of insomnia are associated with a mental disorder.
INSOMNIA SUBTYPES
The ICSD-2 classification lists a number of distinct sleep
disorders associated with insomnia (Box 252). The three
most common insomnia disorders include adjustment
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BOX 252
Insomnia Disorders
SUBTYPES OF INSOMNIA DISORDERS
1. Adjustment Insomnia (Acute Insomnia)
2. Psychophysiologic Insomnia (1215%)
3. Paradoxical Insomnia (<5%)
4. Idiopathic Insomnia (<10%)
5. Insomnia Due to Mental Disorder
6. Inadequate Sleep Hygiene (510%)
7. Behavioral Insomnia of Childhood
8. Insomnia Due to Drug or Substance
9. Insomnia Due to Medical Condition
10. Insomnia Not Due to Substance or Known Physiologic
Condition, Unspecified
11. Physiologic (Organic) Insomnia, Unspecified
OTHER SLEEP DISORDERS ASSOCIATED WITH INSOMNIA
COMPLAINTS
1. Sleep Apnea Syndromes
2. Circadian Rhythm Sleep Disorders
a. Delayed Sleep Phase Typesleep-onset insomnia
b. Advanced Sleep Phase Typeearly AM awakening
c. Irregular Sleep Phase Typeat least 3 sleep episodes
per day
d. Free-Running Typealternating periods of insomnia
and hypersomnia.
3. Restless Legs Syndrome/Periodic Limb Movement
Disorders
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
insomnia, psychophysiologic insomnia, and insomnia due to
a mental disorder. A number of other sleep disorders not
included in this group can also present with complaints of
insomnia (see Box 252). The sleep apnea syndromes can be
associated with repetitive arousal and sleep-maintenance
problems. In patients with sleep apnea, insomnia symp-
toms are more likely to be present in women than in men.1
The circadian rhythm sleep disorders (CRSDs) can also be
associated with insomnia complaints including the delayed
sleep phase syndrome (sleep-onset insomnia) and the
advanced sleep phase syndrome (early morning awaken-
ing). In the delayed sleep phase type, once the affected indi-
viduals are able to fall asleep, they have fairly normal sleep.
In the advanced sleep phase syndrome, individuals fall asleep
early but then awaken in the early morning hours. In CRSD
free-running type, patients may report periods of insomnia
alternating with hypersomnia.1 The restless legs syndrome/
periodic limb movement disorder can also be associated
with symptoms of insomnia or nonrestorative sleep.
Other classifications of insomnia divide disorders into
primary and secondary (co-morbid) insomnia. The Diag-
nostic and Statistical Manual of Mental Disorders, 4th
edition (DSM-IV), lists diagnostic criteria for primary
insomnia (307.42) (Box 253).6 This type of insomnia would
Chapter 25 Insomnia 483
BOX 253
Diagnostic Criteria for Primary Insomnia
A. The predominant complaint is difficulty initiating or
maintaining sleep or nonrestorative sleep for at least 1
month.
B. The sleep disorder causes clinically significant distress
or impairment of social, occupation, or other important
areas of functioning.
C. The sleep disturbance does not occur exclusively
during the course of narcolepsy, breathing-related
sleep disorder, circadian rhythm sleep disorder, or a
parasomnia.
D. The disturbance does not occur exclusively during the
course of another mental disorder (e.g., Major
Depressive Disorder, Generalized Anxiety Disorder, a
delirium).
E. The disturbance is not due to the direct physiologic
effects of a substance (e.g., a drug of abuse, a
medication) or a general medication condition.
From American Psychiatric Association: Diagnostic and Statistical Manual of
Mental Disorders. DSM-IV. Washington, DC: American Psychiatric Association,
1994.
include adjustment insomnia, psychophysiologic insomnia,
paradoxical insomnia, idiopathic insomnia, and inadequate
sleep hygiene. Insomnia associated with a mental disorder is
termed secondary or co-morbid insomnia. The subtypes of
insomnia listed in the ICSD-2 classification are each dis-
cussed in some detail. However, it is helpful to remember the
major characteristics of each type (Table 251) when evalu-
ating patients.
EVALUATION OF INSOMNIA COMPLAINTS
Clinical guidelines for the evaluation and management of
chronic insomnia in adults have been recently published.7
This guideline document provides a succinct discussion that
is a valuable resource for the clinician. Other, more extensive
reviews of evaluation of insomnia and practice parameters
for evaluation have also been published.5,810
A detailed sleep history is the cornerstone of evaluation
of insomnia (Box 254). First, the nature of the primary
sleep complaint (problems with sleep onset, sleep mainte-
nance, or quality) should be defined and the duration of the
complaint determined. The history of the origin of the com-
plaint including age of onset should be explored and particu-
lar life events or stressors at the start of the problem should
be identified. For example, patients with idiopathic insomnia
report problems since childhood or adolescence with an
insidious onset. Patients with psychophysiologic insomnia
may report that chronic insomnia began after a severe illness.
Presleep conditions or activities that could affect sleep
including the bedroom environment, activities near bedtime,
or mental state near bedtime should be explored. The
bedroom environment should be characterized for factors
that might disturb sleep (noise, clock easily seen from the
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484 Chapter 25 Insomnia

TABLE 251
Major Characteristics of Insomnia Types in International Classification of Sleep Disorders, 2nd Edition
INSOMNIA TYPES ESSENTIAL FEATURES CLINICAL CLUES
Adjustment Temporally associated with identifiable stressor. Recent psychological, psychosocial,
Duration less than 3 months. environmental, or physical stressor.
Expected to resolve.
Psychophysiologic Duration at least 1 month. Better sleep in novel environment
Anxiety about sleep. (away from home)
Heightened arousal when in bed. Can fall asleep outside bedroom or
Conditioned sleep-preventing associations (bedroom when not trying to sleep
as stimulus for wake not sleep).
Paradoxical Duration at least 1 month. Objective sleep duration much
Extreme and physiologically improbable complaints: greater than reported.
I never sleep. No or rare naps.
Despite report of little sleep, relatively minor daytime
impairment.
Idiopathic Onset in infancy or childhood. Lifelong insomnia without
No identifiable precipitant. remissions.
No period of sustained remission. Insidious onset.
Associated with a mental Insomnia present for at least 1 month. Insomnia waxes and wanes with
disorder Mental disorder has been diagnosed. mental disorder.
Temporally associated with mental disorder (can
precede by a few days of weeks).
Inadequate sleep hygiene Improper sleep scheduling. Variable bedtime and wake times.
Use of products that disturb sleep near bedtime. Napping.
Stimulating activities near bedtime.
Use of the bed for nonsleep activities.
Behavioral insomnia of Falling asleep is an extended process. Nighttime awakenings require
childhood Sleep-onset associations demanding. caregiver for return to sleep.
sleep association type In absence of associated factors, sleep onset delayed.
Behavioral insomnia of Difficulty initiating or maintaining sleep Caregiver demonstrates
childhood Refusal to go to bed or return to bed after awakening. insufficient limit setting to
limit-setting type Caregiver demonstrates insufficient limit setting to establish appropriate behavior.
establish appropriate behavior.
Adapted from Schutte-Rodin S, Broch L, Buysee D, et al: Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med
2008;4:487504.

bed, extreme hot or cold temperature). Activities near
bedtime, including working late on the computer, drinking
caffeinated beverages or alcohol in the evening, or exercise
near bedtime, may impair the ability to sleep. The mental
status at bedtime should be explored. Often, patients began
worrying about their stresses and problems when retiring for
the night. The presence or absence of nocturnal symptoms
including snoring, gasping during sleep, symptoms of the
restless legs syndrome, and body movements should be
evaluated.
The sleep-wake schedule should be determined by report
including variability of bedtime and rise time as well as the
frequency and duration of naps. Factors that worsen or
improve sleep should be detailed. For example, some patients
with psychophysiologic insomnia report sleeping better in a
novel environment (reverse first-night effect).11 Patient
recall can be supplemented by sleep logs and/or actigraphy
as discussed in a following section. Daytime function should
be discussed with emphasis on possible consequences of
insomnia. Reports of daytime fatigue or impaired cognition
and mood are more common than true daytime sleepiness.
True daytime sleepiness should trigger suspicion for addi-
tional sleep problems such as sleep apnea, narcolepsy, or
depression. Daytime activities that may affect sleep such as
the amount of caffeine, alcohol, exercise, sunlight exposure,
and napping should be detailed. A general medical and psy-
chiatric history is important to identify mental or medical
conditions that may affect sleep. A detailed medication
history including over-the-counter medications and sub-
stances of abuse is extremely important.
A physical examination and a general medical history
including appropriate laboratory (if not recently performed)
should rule out obvious medical causes of insomnia. Exami-
nation of the upper airway showing a high Mallampati score
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 Chapter 25 Insomnia 485

BOX 254 (upper airway narrowing)12 might trigger suspicions of

Evaluation of Insomnia obstructive sleep apnea.

1. SLEEP HISTORY Questionnaires, Sleep Logs, and Actigraphy

A. Define primary complaint Supporting information from questionnaires (mood, cogni-
Delayed sleep onset. tion about insomnia), sleep logs, and actigraphy may be
Sleep maintenance problems. helpful in evaluating patients with insomnia (Table 252).
Frequent awakenings/early AM awakening. These may supplement other information obtained from the
Nonrestorative sleep. sleep history. Assessing the patients attitudes about sleep and
B. Define time course of complaintage of onset, the sleep problem is as important as documenting the degree
precipitating event, or stressor.
of sleep disturbance. In addition, some patients are hesitant
C. Presleep conditions (prebedtime activities, bedroom
to admit to feelings of depression. Sleep logs and actigraphy
environment, physical and mental status before sleep).
provide a more accurate estimate of the patients sleep quan-
D. Nocturnal symptoms (awakenings, physical or mental
tity than is possible from patient recall.
symptoms including snoring or body movements).
E. Sleep-wake scheduleby patient report including
variability, naps. Questionnaires
F. Daytime functionconsequences of insomnia A number of questionnaires have been used to evaluate
Sleepiness versus fatigue. patients with insomnia. The Epworth Sleepiness Scale, as
Impairment of mood, cognitive dysfunction, quality of discussed in Chapter 12, is used to assess subjective estimates
life. of propensity to fall asleep in common situations.13 The Pitts-
G. Daytime activities relevant for sleep burgh Sleep Quality Index (PSQI) is a 24-item self-report
Sunlight exposure, exercise. measure of general sleep quality that specifically addresses
Napping. the preceding 1-month period. The PSQI evaluates seven
Work schedule and disturbance. domains: duration of sleep, sleep disturbance, sleep-onset
Caffeine and alcohol intake. latency, daytime dysfunction due to sleepiness, sleep effi-
H. Medical and psychiatric conditions ciency, need for medications to sleep, and overall sleep
Medications that may affect sleep. quality. The PSQI yields a global score and seven component
Chronic pain. scores (poor sleep: global score > 5).14,15 The questionnaire
has been shown to discriminate healthy patients, patients
2. PHYSICAL AND MENTAL STATUS EXAMINATION
with depression, and patients with sleep disorders. It was not
3. SUPPORTING INFORMATION designed specifically for insomnia but has been used in
A. Sleep/mood questionnaires insomnia assessment and treatment studies. Detailed instruc-
Epworth Sleepiness Scale. tions for use and scoring of the PSQI are available at the
Dysfunctional Beliefs and Attitudes about Sleep. University of Pittsburgh Sleep Medicine Institute website:
Pittsburgh Sleep Quality Index. http://www.sleep.pitt.edu/content.asp?id=1484&subid=2316
B. Sleep log for 2 weeksattention to sleep and wake time The Beck Depression Inventory (BDI-I or BDI-II) is a
variability, general patterns. 21-item self-report inventory used to measure manifesta-
C. Actigraphy. tions of depression, each item being scored from 0 to 3.16,17
Higher total scores indicate more severe depressive symp-
4. SLEEP STUDYNOT ROUTINELY INDICATED
toms. The BDI-II is a revision of the original BDI. The score
Indicated when concerns that another sleep disorder ranges for the BDI-I are 0 to 9: minimal or no depression;
such as sleep apnea is suspected.

TABLE 252
Questionnaires to Evaluate Patients with Insomnia
Epworth Sleepiness Scale Propensity to fall asleep in eight situations (0 never, 1 slight, 2 moderate, 3 high chance)
with a total score 0 to 24. Normal 10.
Beck Depression Inventory BDI-I or BDI-II is a 21-item self-report inventory used to measure depression.
BDI-I scores: Minimal or no depression BDI < 10, moderate to severe depression BDI 19.
BDI-II scores: Minimal or no depression BDI < 14, moderate to severe depression BDI 20.
Pittsburgh Sleep Quality Index A 24-item self-report measure of sleep qualities (poor sleep: global score > 5).
Dysfunctional Beliefs and Attitudes DBAS is a self-rating of 30 statements that is used to assess negative cognitions about
about Sleep Questionnaire sleep. Shorter version of the DBAS-16 also exists (see Appendix 251).
BDI = Beck Depression Inventory; DBAS = Dysfunctional Beliefs and Attitudes about Sleep.
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486 Chapter 25 Insomnia

10 to 18: mild to moderate depression; 19 to 29: moderate Sleep Logs

depression; and 30 to 63: severe depression. The score ranges
for BDI-II are 0 to 13: minimal or no depression; 14 to 19:
mild depression; 20 to 28: moderate depression; and 29 to
63: severe depression. Because primary insomnia and major
depression share some daytime symptoms, the usual cutoff
scores for the BDI might be less specific for depression in
insomnia patients.18 Indeed, one study evaluating the BDI-II
in insomnia patients found that using a cutoff for mild
depression of greater than 14 had a high sensitivity (91%)
but low specificity (66%) for detecting depression. The
authors suggested using a higher cutoff (>17) for mild
depression. Using this cutoff the BDI-II had a 79% specificity
but an 81% sensitivity for identifying depression.
The Dysfunctional Beliefs and Attitudes about Sleep
(DBAS) Questionnaire is a self-rating survey to assess nega-
tive cognitions about sleep.19,20 Reversal of these cognitions is
a goal of the cognitive component of CBT (cognitive behav-
ioral therapy). The original DBAS was a 30-item question-
naire in which patients responded using an analog scale (0,
strongly disagree; 1, 2, 3. . . , to 10, strongly agree). A shorter
version (DBAS-16)20 has recently been validated and is less
time-consuming for patients to complete (Appendix 251).
Having insomnia patients complete a sleep log (sleep diary)
for at least 2 weeks is recommended. Sleep logs are often
more accurate than relying on patient recall of their chronic
sleep patterns. Sleep logs usually follow a question format
(Fig. 251) or time plot graphic format (Fig. 252). The
essential elements include the ability to assess time in bed
(TIB), sleep-onset latency (SOL), total sleep time (TST), and
the amount of wake after sleep onset (WASO). The TIB is the
time period from when the patient gets in bed until the final
time the patient leaves the bed in the morning. The WASO
includes all wake from sleep onset until the patient leaves the
bed in the morning. The patient need report only three
of these four parameters because they are related (TIB =
SOL + TST + WASO). One can compute a sleep efficiency
(= TST 100/TIB) with normal values exceeding 85%. Sleep
logs also typically provide space to record caffeine consump-
tion, bedtime activities, or medications taken for sleep as
well as estimates of sleep quality. Sleep logs are very helpful
in revealing general patterns of the sleep-wake cycle such as
irregular bedtimes and wake times and the amount and fre-
quency of napping. A few characteristic patterns noted in
sleep logs are listed in Table 253.

SLEEP DIARY

Complete before bedtime Complete in the morning

Sleeping I went Last I woke up

Caffeine medication? to bed I got out night, during the Last night,
Bedtime drinks today Activity last of bed this When I woke
I exercised I fell night I slept a
before Alcohol? night morning asleep in up for the day
day > 20 minutes (how total of
bed at? at? I felt:
(0 if none) many (hours)
(give times) (minutes)
PM/AM PM/AM times?)

Day 1 morning morning ( ) refreshed

afternoon afternoon ( ) somewhat

Day of week
times hours refreshed
after within 3
Date supper hours of ( ) fatigued
bedtime
Day 2 morning morning ( ) refreshed
afternoon afternoon ( ) somewhat
Day of week
times hours refreshed
after within 3
Date supper hours of ( ) fatigued
bedtime
Day 3 morning morning ( ) refreshed
afternoon afternoon
Day of week ( ) somewhat
times hours
after within 3 refreshed
Date supper hours of
( ) fatigued
bedtime
Day 4 morning morning
( ) refreshed
afternoon afternoon
Day of week ( ) somewhat
times hours refreshed
after within 3
Date supper hours of
bedtime ( ) fatigued

FIGURE 251 A typical sleep log. From the answers, one can determine the time in bed (TIB), the sleep latency, and the total sleep time. The wake after sleep onset = TIB sleep
latency total sleep time.
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 Chapter 25 Insomnia 487

PM Midnight AM Noon PM
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6

Sun X Mon

Mon X Tues

Tues X Wed

Wed X Thurs

Thurs X Fri

Fri X Sat

Sat X Sun

Sun X Mon

Mon X Tues

X Lights out - trying to sleep Asleep In bed Out of bed

FIGURE 252 A sleep log (diary) shows inadequate sleep hygiene with variable bedtimes and wake times as well as
napping. Note that on Sunday and Wednesday, the sleep latency was prolonged. Once asleep, the patient had no middle of the
night awakenings.

BOX 255
TABLE 253
Some Typical Sleep Log Patterns Selected Recommendations for the Use of
Actigraphy According to American Academy of
Delayed sleep Late bedtime or long sleep latency, Sleep Medicine Practice Parameters (2007 Update)
phase few awakenings, normal sleep
duration on weekends or 1. Actigraphy is a valid method to determine sleep
nonwork/nonschool days. patterns in normal healthy population (Standard) and
in certain sleep disorders. (Option-Guideline)
Inadequate sleep Irregular wake and rise times, naps.
2. Actigraphy is indicated to assist in evaluation of patients
hygiene
with suspected advanced sleep phase syndrome,
Psychophysiologic Long sleep latency, decreased total delayed sleep phase syndrome, and shift work
insomnia sleep time, frequent awakenings. disorder (Guideline); and circadian rhythm disorders,
Variability in sleep quality. including jet lag, and non24-hr sleep/wake CRSD.
(Option)
Paradoxical Nights of minimal or no sleep are
3. When PSG is not available, actigraphy is indicated to
insomnia reported followed by no or few
estimate TST in patients with OSA. (Standard)
naps the next day.
4. Actigraphy is indicated as a method to characterize
circadian rhythm patterns of sleep disorders in
individuals with insomnia including insomnia with
Actigraphy depression. (Option)
Actigraphy involves use of a portable device (often resem- 5. Actigraphy is indicated as a way to determine circadian
bling a watch and typically worn on the wrist) that collects pattern and estimate average daily sleep time in
movement information (activity) over an extended period of individuals complaining of hypersomnia. (Option)
time (Fig. 253). The absence of movement is assumed to be 6. Actigraphy is useful as an outcome measure in
a surrogate of sleep.2129 The use of actigraphy is included in evaluating the response to treatment for circadian
rhythm disorders. (Guideline)
the ICSD-2 diagnostic criteria for several CRSDs, paradoxi-
7. Actigraphy is useful for evaluation of the response to
cal insomnia, and behaviorally induced insufficient sleep
treatment for patients with insomnia, including insomnia
syndrome.1 Practice parameters for use of actigraphy have associated with depression. (Guideline)
been published by the American Academy of Sleep Medicine
CRSD = circadian rhythm sleep disorder; OSA = obstructive sleep apnea;
(AASM).23,29 Some of the recommendations are listed in PSG = polysomnography; TST = total sleep time.
Box 255. Note that, although actigraphy was said to be From Morgenthaler T, Alessi C, Friedman L, et al. Practice parameters for the
indicated for determining the circadian patterns of patients use of actigraphy in the assessment of sleep and sleep disorders: an update
for 2007. Sleep 2007;30:519529.
with insomnia, the practice parameters did not state that
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488 Chapter 25 Insomnia

Normal
100
Activity 50

12 14 16 18 20 22 24 02 04 06 08 10 12
Wake Sleep
12 14 16 18 20 22 24 02 04 06 08 10 12
In bed
12 14 16 18 20 22 24 02 04 06 08 10 12

Disturbed sleep
100
Activity 50

12 14 16 18 20 22 24 02 04 06 08 10 12
Wake Sleep
12 14 16 18 20 22 24 02 04 06 08 10 12
In bed
12 14 16 18 20 22 24 02 04 06 08 10 12

FIGURE 253 Examples of actigraphy in a normal subject and a patient with disturbed sleep. Top, Normal subject. Measures of activity,
actigraphic estimates of wake and sleep, and sleep log reported time in bed are displayed. Bottom, A patient with disturbed sleep. Note
persistent activity during the sleep period. In the wake sleep data, periods identified as wake (thin line) are above periods of sleep (thicker
line). Adapted from Crdoba J, Cabrera J, Lataif L, et al: High prevalence of sleep disturbance in cirrhosis. Hepatology 1998;27:339345.

actigraphy was indicated as a routine evaluation of patients
with insomnia.
Actigraphy does not measure sleep as defined by electro-
encephalogram (EEG)/electro-oculogram (EOG)/chin elec-
tromyogram (EMG) criteria or the subjective experience of
sleep (as measured by sleep logs and questionnaires). There-
fore, it is not surprising that estimates of TST, wake time, and
the sleep latency from sleep logs and actigraphy may differ
from polysomnography (PSG) findings. Algorithms have
been developed to estimate TST and WASO from the activity
data. Modern actigraphic software allows the clinician to
mark periods of possible sleep (rest periods). The software
then provides automatic estimates of periods of sleep and
wake. These can be edited if desired. However, there are
limitations to the accuracy of these estimates. Actigraphic
estimates of sleep duration, WASO, and sleep latency are
more accurate in normal individuals than in patients with
insomnia. Periods of low activity in which patients lay quietly
in bed but are awake may be scored as sleep by actigraphy
software. When performing actigraphy, it is essential to
require patients to complete a sleep log (e.g., lights off, lights
on, out of bed, actigraph off for shower; TST; sleep latency).
This information enables a correct interpretation of acti-
graphic tracings. For example, total absence of movement
usually indicates that the actigraph has been removed
(shower, swimming), but here patient logs are essential to
verify device removal. If the actigraphic estimate of TST
far exceeds patient estimates, this would suggest paradoxi-
cal insomnia. Many modern wrist actigraph devices also
provide the capability of recording the amount of ambient
light. This is useful in patients with CRSDs in whom light
exposure may either exacerbate or improve the underlying
disorder. Some actigraphy devices also have event markers
that the patient can press when getting in bed, trying to sleep,
or after awakening in the morning.
Sleep logs and actigraphy provide complementary
information. In a study of patients with insomnia undergo-
ing treatment, Vallires and Morin24 compared findings from
actigraphy and sleep logs with PSG (Fig. 254A). Both actig-
raphy and sleep logs underestimated TST and overestimated
wake time. Actigraphy underestimated the sleep latency and
sleep logs overestimated the sleep latency. These authors
found actigraphy to be more sensitive at detecting treatment
effects than sleep logs. In contrast, Sivertsen and coworkers25
found different results in a group of older adults treated for
primary insomnia (expected to have more wake time).
Actigraphy slightly overestimated TST and underestimated
wake (see Fig. 254B). In this study, actigraphy provided a
better estimate of TST than of wake time.
Polysomnography
PSG is not indicated for the routine assessment of insom-
nia.9,10 However, if there is a suspicion for sleep apnea, peri-
odic limb movement disorder, or a parasomnia, a PSG may
be useful. The 2003 AASM practice parameters for the role
of PSG in insomnia stated polysomnography is indicated
when the initial diagnosis (insomnia) is uncertain, treatment
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 Chapter 25 Insomnia 489

Log/PSG
Act/PSG Log/PSG

2 2

Act/PSG

Act/PSG Log/PSG
1 1

Act/PSG

0 0
TST Wake Sleep TST Wake Sleep
A latency B latency

FIGURE 254 A, A plot of the ratios of actigraphic (Act)/PSG (polysomnography) and sleep log (Log)/PSG estimates of total
sleep time (TST), wake, and sleep latency from the data of a study by Vallries and Morin in patients with insomnia. Both
actigraphy and sleep logs slightly underestimated the total sleep time but overestimated wake time. Sleep logs overestimated
sleep latency while actigraphy underestimated sleep latency (laying in bed still but awake). B, A plot of data from a study of
older insomnias by Sivertsen and coworkers. Actigraphy slightly overestimated TST but underestimated wake and sleep latency.
A, From Vallires A, Morin CM: Actigraphy in the assessment of insomnia. Sleep 2003;26:902906. B, Sivertsen B, Omvik S, Havik
OE, et al: A comparison of actigraphy and polysomnography in older adults treated for chronic primary insomnia. Sleep
2006;29:13531358.

fails (either behavioral or pharmacologic), or precipitous BOX 256

arousals occur with violent or injurious behavior (Guide-
line).10 When PSG is performed, typical findings (Box 256)
in patients with insomnia include a long sleep latency
(>30 min), reduced TST, increased WASO, and a reduced
sleep efficiency. A long rapid eye movement (REM) latency,
high arousal index, increased stage N1, and decreased stage
N3 sleep may also be noted. In patients with paradoxical
insomnia, the objective sleep abnormality is much less
severe than reported. It is not unusual for such patients to
report little or no sleep following a PSG documenting only
mild to moderate decrements in the TST. In some patients
with psychophysiologic insomnia, the reverse first-night
effect11 may be noted. In these patients, the sleep quality in
the sleep center is better than that reported at home. It is
essential to have all patients complete questionnaires assess-
ing subjective sleep (estimate TST, sleep latency, sleep
quality) after PSG.
PHYSIOLOGIC FINDINGS
IN PRIMARY INSOMNIA
Some but not all studies have documented increased high-
frequency EEG activity, increased whole body and brain
metabolic activity, elevated heart rate, and sympathetic
nervous system activation (decreased heart rate variability)
during both day and night in patients with insomnia. These
findings suggest that patients with insomnia are in a state of
hyperarousal.30 Of special interest, functional neuroimaging
has found greater global cerebral glucose metabolism during
sleep and while awake and a smaller decline in relative
metabolism from waking to sleep in wake-promoting regions
in patients with insomnia compared with normal controls.31
In addition, reduced metabolism was found in the prefrontal
Typical Polysomnography Findings in Patients
with Insomnia
Increased sleep latency (>30 min)
Decreased TST
Decreased sleep efficiency
Increased stage N1 (%TST)
Decreased stage N3 (%TST)
Increased REM latency
Decreased REM latency (depression)
REM = rapid eye movement; TST = total sleep time.
cortex of patients with primary insomnia while awake. It is
not clear whether these findings represent cause or effect. A
recent study of magnetic resonance spectroscopy found a
global reduction in gamma-aminobutyric acid (GABA) in
nonmedicated patients with primary insomnia compared
with normal controls.32 This neurotransmitter is generally
inhibitory and higher levels would be expected to promote
sleep.
INDIVIDUAL INSOMNIA SUBTYPES
Adjustment Insomnia (Acute Insomnia)
Adjustment insomnia, at least in milder forms, is experi-
enced by a large percentage of otherwise normal sleepers at
some time in their lives. The 1-year prevalence of adjustment
insomnia in adults is 15% to 20%. The problem resolves
with time in most cases. If the insomnia persists beyond
3 months, it is considered a chronic insomnia. Some
cases of psychophysiologic insomnia may have started as
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490 Chapter 25 Insomnia
adjustment insomnia. Most patients with adjustment insom-
nia are not evaluated by a sleep specialist. However, they may
request hypnotic medication from their primary care physi-
cian or self-medicate with over-the-counter sleep aids.
Key Features
Adjustment insomnia is a disorder of less than 3 months
duration that is in response to a definitely identifiable event
(Box 257). It is expected to resolve but may require treat-
ment if a significant impact on sleep and daytime function-
ing is noted.
PSG Findings
PSG findings have not been reported.
Differential Diagnosis
Psychophysiologic and paradoxical insomnia typically last
longer than 3 months. Insomnia due to medical disorder or
medication is temporally associated with starting a medica-
tion or the onset of the medical disorder. Insomnia due to
mental disorder typically lasts longer than 3 months and
waxes and wanes with the mental disorder. Patients with
adjustment insomnia can develop a chronic insomnia disor-
der. Some patients with psychophysiologic insomnia report
the onset of their problem after an acute stress. Insomnia due
to a mental disorder may develop if the patient with adjust-
ment insomnia develops depression as a result of the acute
stressor.
Treatment
Benzodiazepine receptor agonists (BZRAs), ramelteon,
anxiolytics, or counseling are used to treat adjustment
insomnia (if necessary).
Psychophysiologic Insomnia
Psychophysiologic insomnia is the most common primary
insomnia type seen in sleep clinics and it is often called
conditioned or learned insomnia.
BOX 257
Adjustment InsomniaDiagnostic Criteria
A. Patients symptoms meet criteria for insomnia.
B. The sleep disturbance is temporally associated with an
identifiable stressor that is psychological, psychosocial,
interpersonal, environmental, or physical in nature.
C. The sleep disturbance is expected to resolve when the
acute stressor resolves or when the individual adjusts to
the stressor.
D. The sleep disturbance lasts less than three months.
E. The sleep disturbance is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, medication use, or substance abuse.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Key Features
Conditioned sleep difficulty, heightened arousal in bed, and
learned sleep-preventing associations are the essential char-
acteristics of this disorder. Mental arousal (racing mind/
thoughts) occurring when trying to go to sleep is a common
complaint. The patient becomes conditioned so that the
bedroom is a cue to develop tension, anxiety, and inability
to fall asleep. Some patients sleep better away from home.
Patients typically can fall asleep during monotonous activi-
ties but not after getting into bed and trying to sleep. For
example, a patient may fall asleep while watching television
in the living room but become wide awake after entering the
bedroom and attempting to sleep. This disorder may start
after a precipitating event (death in family, job stress) but
then persists owing to perpetuating behaviors even after the
precipitating event has resolved. Other patients report a slow
onset of symptoms. Patients may report a lifelong pattern of
being light sleepers or episodically poor sleep (Box 258).
Incidence
Psychophysiologic insomnia is present in 1% to 2% of the
general population and 12% to 15% of patients seen in sleep
centers. This disorder is more common in women than in
men.
If left untreated, the disorder may persist for decades with
periodic worsening.
Objective Findings
Polysomnography Although sleep studies are not indicated
for evaluation of most patients with insomnia, typical
BOX 258
Psychophysiologic InsomniaDiagnostic Criteria
A. Patients symptoms meet the criteria for insomnia.
B. Duration of at least 1 month.
C. Evidence of conditioned sleep difficulty and/or
heightened arousal in bed as indicated by one or more
of the following:
i. Excessive focus on sleep, anxiety about sleep.
ii. Difficulty falling asleep in bed at desired bedtime
or during planned naps BUT no difficulty falling
asleep during other monotonous activities when not
intending to sleep.
iii. Ability to sleep better away from home.
iv. Mental arousal in bed characterized by either
intrusive thoughts or a perceived inability to
volitionally cease sleep-preventing mental activity.
v. Heightened somatic tension in bed reflected by a
perceived inability to relax the body sufficiently to
allow the onset of sleep.
D. The sleep disturbance is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, medication use, or substance abuse.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
DaneshGroup.com

findings include a prolonged sleep latency (>30 min),
increased WASO, and decreased sleep efficiency. Sometimes,
the reverse first-night effect is noted with better sleep in the
sleep center than at home. Patients may underestimate their
sleep duration but not the gross underestimation seen in
paradoxical insomnia.
Multiple Sleep Latency Test The sleep latency usually is in the
range of 10 to 15 minutes.
Sleep Logs Sleep logs typically show a long sleep latency,
reduced TST, increased WASO, and a large number of
nocturnal awakenings. Poor sleep quality is often reported.
Typically, there is considerable night-to-night variability
in sleep quality. There may also be evidence of poor sleep
hygiene with prolonged time in bed, napping, and variabi-
lity in wake times.
Actigraphy Findings may overestimate or underestimate TST
when compared with PSG. Actigraphy typically provides a
better estimate of TST than of wake time. Typical actigraphic
findings would substantiate patient reports and findings
from sleep logs.
Treatment CBT for insomnia and pharmacotherapy are treat-
ment options. These are discussed in a later section of this
chapter.
Paradoxical Insomnia (Sleep State
Misperception)
Key Features
The severe degree of sleep disturbance reported in patients
with paradoxical insomnia (formerly called sleep state
misperception) is out of proportion to the relatively mild
daytime impairment and the severity of sleep disturbance
documented on PSG.
Patients often report little or no sleep on many nights
followed by days with relatively minimal dysfunction and no
napping. In addition, patients with paradoxical insomnia
often report hearing every noise in the house while in the
bedroom and/or actively thinking for the entire night.
Daytime impairment reported is consistent with other types
of insomnia but is much less severe than expected, given
the severe level of sleep deprivation reported. For example,
there are no intrusive sleep episodes or serious mishaps due
to loss of alertness, even following nights reportedly without
sleep (Box 259).
Incidence
Paradoxical insomnia is found in less than 5% of insomnia
patients evaluated in sleep clinics.1
Objective Findings
Sleep Log Data Sleep log information is usually consistent
with the patients complaints, but NOT consistent with
objective evidence (from PSG or actigraphic data). There
may be nights with little or no sleep reported followed by
days with no napping.
Chapter 25 Insomnia 491
BOX 259
Paradoxical Insomnia (Sleep State
Misperception)Diagnostic Criteria
A. Symptoms meet criteria for insomnia.
B. Insomnia is present for at least 1 month.
C. One or more of the following criteria apply:
i. Chronic pattern of little or no sleep most nights with
rare nights during which relatively normal amount of
sleep is obtained.
ii. Sleep log data during 1 or more weeks of monitoring
show an average sleep time well below published
age-adjusted normative values, often with no sleep
at all indicated for several nights per week: typically
there is an absence of naps following such nights.
iii. The patient shows a consistent mismatch between
objective findings from PSG or actigraphy and
subjective sleep estimates derived from either
sleep report or sleep diary.
D. At least one of the following is observed:
i. Constant or near-constant awareness of
environmental stimuli throughout most nights.
ii. The patient reports a pattern of conscious thoughts
or rumination throughout most nights while
maintaining a recumbent posture.
E. Daytime impairment reported is consistent with other
types of insomnia subtypes, it is much less severe than
expected, given the extreme level of sleep deprivation
reported; there is no report of intrusive daytime sleep
episodes, disorientation, or serious mishaps due to
marked loss of alertness or vigilance, even following
reportedly sleepless nights.
F. The sleep disturbance is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, medication use, or substance abuse.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
PSG Findings PSG findings indicated lack of significant defi-
cits in TST or an excessively prolonged sleep latency. If
abnormalities are noted on the PSG, they are less severe than
reported by the patient.
Reported sleep latency and WASO at least 1.5 times the
PSG values.
Multiple Sleep Latency Test The sleep latency in patients
with paradoxical insomnia is typically normal or slightly
decreased.
Differential Diagnosis
Unlike idiopathic insomnia, paradoxical insomnia does
not begin in childhood. In contrast to psychophysiologic
insomnia, patients with paradoxical insomnia are more
prone to report little or NO sleep on many nights. However,
some patients with psychophysiologic insomnia also
underestimate their nocturnal sleep. Whereas patients with
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492 Chapter 25 Insomnia
paradoxical insomnia often report being aware of the envi-
ronment for the entire night or ruminating on problems,
they tend to have less prominent sleep-preventing asso-
ciations compared with patients with psychophysiologic
insomnia.
Treatment
CBT of insomnia (CBTI), pharmacotherapy, or both are
recommended.
Idiopathic Insomnia
Idiopathic insomnia is also called childhood-onset insomnia.
The patient usually recalls the insidious onset of the insom-
nia problems in childhood. The history is one of lifelong
insomnia problems (Box 2510).
Key Features
Patients with idiopathic insomnia report this problem since
childhood with no periods of significant remission. There is
no identifiable cause or precipitating factor. The onset is
often insidious.
Epidemiology
Idiopathic insomnia occurs in less than 10% of patients with
insomnia. Idiopathic insomnia is a rare disorder occurring
in only approximately 0.7% of adolescents.1
Objective Findings
Polysomnography PSG findings include a long sleep latency,
increased WASO, reduced TST, and low sleep efficiency.
These findings are not specific for idiopathic insomnia.
Sleep Log Findings from a sleep log are typically consistent
with the patients complaints.
Differential Diagnosis
Whereas idiopathic insomnia has an insidious onset in
childhood, psychophysiologic insomnia starts in adulthood
and the time of onset can often be defined. In paradoxical
BOX 2510
Idiopathic InsomniaDiagnostic Criteria
A. The patients symptoms meet criteria for insomnia.
B. The course of the disorder is chronic, as indicated by
each of the following:
a. Onset during infancy or childhood.
b. No identifiable precipitant or cause.
c. Persistent course with no periods of sustained
remission.
C. The sleep disturbance is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, medication use, or substance abuse.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
insomnia, a more severe abnormality of sleep is usually
reported and the disorder does not start at an early age.
Treatment
CBTI, pharmacotherapy, or both are options. No large
studies of treatment outcomes have been published.
Insomnia Due to a Mental Disorder
Insomnia due to mental disorder (IDMD) is the most
common form of insomnia seen by sleep physicians (Box
2511). Many times, patients have fixated on the insomnia
problems while ignoring (denying) or minimizing their
other symptoms of depression.
Key Features
The insomnia is viewed as a consequence of the mental dis-
order (e.g., depression) and shares the course of the disorder
(waxing and waning together). However, insomnia can actu-
ally precede the development of depression in some patients.
Of note, insomnia complaints are very common in mood
disorders and are often considered secondary (co-morbid)
to the mood disorder. A separate diagnosis of insomnia due
to mental disorder (IDMD) is made only if the insomnia is
significant enough to warrant special attention. Common
mental disorders associated with IDMD include major
depression, bipolar disorder, and anxiety disorder. In anxiety
disorders, prominent sleep-onset insomnia is usually present.
In depressive disorders, especially in older patients, the
sleep disturbance is characterized by prominent sleep-
maintenance insomnia and early morning awakening.
Younger patients with depression may experience more
prominent sleep-onset insomnia.
Epidemiology
IDMD is the most common cause of insomnia in
patients presenting to sleep disorder centers complaining
BOX 2511
Insomnia Due to Mental Disorder
Diagnostic Criteria
A. Patients symptoms meet criteria for insomnia.
B. The insomnia is present for at least 1 month.
C. A mental disorder has been diagnosed by standard
criteria (Diagnostic and Statistical Manual of Mental
Disorders, 4th edition).
D. Insomnia is temporally associated with the mental
disorder; however, in some cases, insomnia may appear
a few days or weeks before the emergence of the
underlying mental disorder.
E. The sleep disturbance is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, medication use, or substance abuse.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
DaneshGroup.com

of insomnia. The disorder is more likely in women than
in men. IDMD occurs in up to 3% of the population.
Objective Findings
Polysomnography PSG if performed shows no specific find-
ings as far as a sleep latency, TST, or WASO. Patients with
depression may have a short REM latency.
Beck Depression Inventory This inventory reveals an elevated
score (BDI-I > 10, BDI-II > 14).
Sleep Logs Sleep logs may show a long sleep latency, de-
creased TST, early morning awakening, or frequent awaken-
ings. These findings are usually consistent with patient
complaints.
Treatment
Treatment of the underlying mental disorder may ultimately
improve sleep. However, because the sleep complaints are
so prominent, treatment with a hypnotic or the addition of
a sedating antidepressant is often needed. CBT of IDMD is
also effective. Drug treatment of patients with insomnia
and mental disorders is discussed in more detail in the
Pharmacologic Treatment of Insomnia section.
Inadequate Sleep Hygiene
Key Features
This disorder is characterized by behaviors that can poten-
tially disrupt sleep such as exercise or ingestion of caffeine
or alcohol near bedtime (Box 2512). Patients often have
irregular bedtimes and wake times and spend too much time
in bed. Napping is another behavior that makes nocturnal
sleep more difficult. Recommendations for good sleep
hygiene are listed in Box 2513.
Epidemiology
The importance of poor sleep hygiene in the development of
insomnia is unknown. Although sleep hygiene education is
a part of most treatment programs for insomnia, there is no
evidence for effectiveness of this intervention when used
alone. Insomnia due to inadequate sleep hygiene may
develop in adolescence or adulthood. Insomnia due to inad-
equate sleep hygiene occurs in approximately 5% to 10% of
insomnias evaluated in a sleep center. The condition is
present in 1% to 2% of adolescents and young adults.
Objective Findings
Sleep Log A typical sleep log of a patient with poor sleep
hygiene is shown in Figure 252. Findings include variation
in wake time, napping, and sleeping much longer on the
weekend. Inappropriate use of caffeine and use of over-
the-counter medications or alcohol may also be reported
on sleep logs.
Long-term Complications Patients with poor sleep hygiene may
develop caffeine or alcohol dependence or eventually psy-
chophysiologic insomnia.
Chapter 25 Insomnia 493
BOX 2512
Inadequate Sleep HygieneDiagnostic Criteria
A. Symptoms meet criteria for insomnia.
B. The insomnia is present for at least 1 month.
C. Inadequate sleep hygiene practices are evident as
indicated by the presence of at least one of the
following:
i. Improper sleep scheduling consisting of frequent
daytime napping, selecting highly variable bedtimes
or rising times, or spending excessive amount of
time in bed.
ii. Routine use of products containing alcohol, nicotine,
or caffeine, especially in periods preceding bedtime.
iii. Engagement in mentally stimulating, physically
activating, or emotionally upsetting activities too
close to bedtime.
iv. Frequent use of the bed for activities other than
sleep (TV watching, reading, studying, snacking,
thinking, planning).
v. Failure to maintain a comfortable sleeping
environment.
D. The sleep disturbance is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, medication use, or substance abuse.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
BOX 2513
Good Sleep Hygiene Practices
Limit caffeine consumption to before noon.
No exercise within 2 hours of bedtime.
Use the bed only for sleep and sex (avoid excessive time
in bed).
Maintain regular waking times.
Bedroom should be quiet and cool.
Avoid stimulating activity near bedtime.
Treatment
Education about good sleep hygiene and CBTI, if necessary,
are recommended. As noted previously, there is no evidence
that education about sleep hygiene alone is effective treat-
ment for the insomnia syndromes. In patients with diffi-
culties entirely due to poor (inadequate) sleep hygiene,
one might expect improvement if their sleep habits were
improved.
Behavioral Insomnia of Childhood
The behavioral insomnia of childhood (BIOC) including
bedtime problems and nighttime awakenings is highly prev-
alent in young children, occurring in approximately 20% to
30% of infants, toddlers, and preschoolers.1,33,34 Although
BIOC is typically divided into sleep-onset association type
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494 Chapter 25 Insomnia
and limit-setting type, there is considerable overlap in most
children. If the major emphasis is on refusal to go to bed
(getting out of bed, verbal protests, crying, and attention-
seeking behavior), then limit-setting is the main problem. If
sleep either at bedtime or after awakenings requires certain
behaviors (rocking, feeding, parental presence in the
bedroom), then sleep association is the predominant type.
Due to variations in culture patterns, what degree of BIOC
type behaviors really constitutes a problem is highly variable.
In addition, the main complaint is from the caregiver and
not the child.
Key Features
The diagnostic criteria for BIOC are listed in Box 2514.1
For the sleep-onset association type, falling asleep is an
extended process that requires special conditions. Sleep
onset at night is typically prolonged, problematic, and often
demanding for the caregiver. Nighttime awakenings require
caregiver interventions for the child to return to sleep. In
limit-setting disorder, the child has difficulty initiating
or maintaining sleep. An essential component is that the
caregiver demonstrates insufficient or inappropriate limit-
setting to establish appropriate sleeping behavior in the
child.
BOX 2514
Behavioral Insomnia of Childhood
Diagnostic Criteria
A. Childs symptoms meet the criteria for insomnia based
upon report of the parents or other adult caregivers.
B. Pattern consistent with sleep-onset association or
limit-setting type of insomnia described below:
1. Sleep-onset association type includes each of the
following:
i. Falling asleep in an extended process that
requires special conditions.
ii. Sleep-onset associations are highly problematic or
demanding.
iii. In the absence of the associated condition, sleep
onset is significantly delayed or sleep is otherwise
disrupted.
iv. Nighttime awakenings require caregiver
intervention for the child to return to sleep.
2. Limit-setting type includes EACH of the following:
i. Individual has difficulty initiating or maintaining
sleep.
ii. Individual stalls or refuses to go to bed at an
appropriate time or refuses to return to bed
following a nighttime awakening.
iii. The caregiver demonstrates insufficient or
inappropriate limit setting to establish
appropriate sleeping behavior in the child.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Treatment
Whereas the treatment of adult insomnia is discussed in
detail in later sections, a detailed discussion of the treatment
of BIOC is presented here due to the unique approaches
indicated for this problem (Table 254 and Box 2515).
In 2006, the AASM published practice parameters for
treatment of BIOC33 based on a systematic review.34 In
behavioral therapy, extinction means reducing a given behav-
iors occurrence by withholding or eliminating any reinforce-
ments for that behavior. Several formats are relevant to
behavioral insomnia.
Unmodified Extinction The goal of this technique is to reduce
undesired behavior (prolonged bedtime protests) by elimi-
nating any reinforcement (parental attention) of the behav-
ior. This involves putting the child to bed and then not
responding to any crying or protests. Unmodified extinction
has limited parental acceptance.
Modified Extinction In this procedure, reinforcements are not
completely eliminated but reduced in value. For example,
BOX 2515
Recommendations for Behavioral Treatment of
Behavioral Insomnia of Childhood
1. Behavioral interventions are effective and
recommended in the treatment of bedtime problems
and night wakings in young children. (Standard)
2. Unmodified extinction and extinction of undesired
behavior with parental presence (modified extinction)
are effective and recommend therapies in the treatment
of bedtime problems and night wakings.
3. Parental education/prevention is an effective and
recommended therapy in treatment of bedtime
problems and night wakings. (Standard)
4. Graduated extinction of undesired behavior is an
effective and recommended therapy in the treatment of
bedtime problems and night wakings. (Guideline)
5. Delayed bedtime with removal from bed (if no sleep)
and positive routines is an effective therapy in the
treatment of bedtime problems and night wakings.
(Guideline)
6. The use of scheduled awakenings is an effective and
recommended therapy in the treatment of bedtime
problems and night wakings. (Guideline)
7. Insufficient evidence was available to recommend any
technique as more effective. (Option)
8. Behavioral interventions are recommended and effective
in improving secondary outcomes (childs daytime
functioning, parental well-being) in children with
bedtime problems and night wakings. (Guideline)
Levels of Evidence: Standard > Guideline > Option.
From Morgenthaler TI, Owens J, Alessi C, et al: Practice parameters for
behavioral treatment of bedtime problems and night wakenings in infants
and young children. Sleep 2006;29:12771281.
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 Chapter 25 Insomnia 495

TABLE 254
Techniques Used for Behavioral Treatment of Insomnia of Childhood
TECHNIQUE
Unmodified extinction
Graduated extinction
Scheduled awakenings
Positive routines
Delayed (faded) bedtime
Response cost
Parental education and
prevention
Adapted from Mindell JA, Kuhn B, Lewin DS, et al: Behavioral treatment of bedtime problems and night wakings in infants and young children. An American
Academy of Sleep Medicine Review. Sleep 2006;29:12631276.
DESCRIPTION RATIONALE
Involves parents putting the child to bed at a designated Reduce undesired behaviors (e.g.,
bedtime and then ignoring the child until morning crying, screaming) by eliminating
(parents continue to monitor for safety issues). parental attention (reinforcer).
Involves parents ignoring bedtime crying and tantrums for Enable a child to develop self-
predetermined periods before briefly checking on the soothing skills and be able to
child. A progressive (graduated) checking schedule (e.g., fall asleep independently
5 min, then 10 min) or fixed checking schedule (e.g., without undesirable sleep
every 5 min) may be used. associations.
Involves parents preemptively awakening their child, prior Prevents nightly reinforcement for
to a typical spontaneous awakening, and providing the undesirable behaviors involved
usual responses (e.g., feeding, rocking, soothing) as if with waking.
child had awakened spontaneously.
Parents develop set bedtime routines characterized by Removes negative stimuli
enjoyable and quiet activities to establish a behavioral associated with bedtime.
chain leading up to sleep onset.
Temporarily delaying the bedtime to more closely coincide Reduced arousal at bedtime
with the childs natural sleep-onset time, the fading
(bedtime) is moved earlier as the child gains success
falling asleep quietly.
Response cost involves removing the child from bed for A type of stimulus control for child:
prescribed brief periods of time if the child does not fall the bedroom is a place for sleep
asleep within a prescribed time. not crying/attention seeking.
Involves parent education to prevent the occurrence of the Preventing problems before they
development of sleep problems. Behavioral interventions occur.
are incorporated into these parent education programs.

extinction with parental presence involves the parent staying
in the childs bedroom but not talking with the child, rocking
the child, or other behaviors.
Graduated Extinction Parents are instructed to ignore bedtime
crying and tantrums for specified periods according to a
fixed schedule of progressively longer intervals and to avoid
reinforcing protest behavior. For example, suppose a child
typically starts crying when placed in the crib. On subse-
quent nights, bedtime crying is ignored for 10, then 20, then
30, and 60 minutes or more on successive nights.
For these techniques to be effective, parents must be moti-
vated and consistent. It is important that the caregivers
choose an approach that they are comfortable with and then
apply it every night.
Insomnia Due to Drug or Substance
Insomnia due to drug or substance implies that the insomnia
complaints are associated with the use of or withdrawal from
a medication or substance. Some patients may often be able
to relate the onset of sleep problems with the start of a new
medication. In others, the onset is more insidious and may
not be noticed.
Key Features
Patients must have ongoing use of a drug or substance asso-
ciated with symptoms of insomnia. The insomnia can also
occur on withdrawal from the agent. In recovering alcohol-
ics, sleep disturbance may persist for many months after
the start of abstinence (Box 2516).
Epidemiology
Insomnia complaints due to medications or substances are
very common. Caffeine is a widely used stimulant that may
affect sleep for hours after ingestion. The half-life of caffeine
varies from 3 to 7 hours and is longer at higher doses.35
Alcohol may aid sleep onset but tends to cause frequent
awakenings in the second part of the night.36
Causes
A large number of medications can be associated with
insomnia (Table 255).37 Nonsedating antidepressants, anti-
convulsants, beta blockers, bronchodilators, and stimulants/
alerting agents can all be associated with insomnia. Medica-
tions that cause nightmares may also result in insomnia.
Beta Blockers Because beta blockers are frequently used to
treat patients with cardiovascular disease, it is important for
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496 Chapter 25 Insomnia

BOX 2516 TABLE 255

Insomnia Due to Drug or Substance Medications and Substances Known to Cause
Diagnostic Criteria Insomnia

A. Symptoms meet criteria for insomnia. ANTICONVULSANTS STEROIDS

B. The insomnia is present for at least 1 month. Lamotrigine Prednisone
C. One of the following applies:
ANTIDEPRESSANTS DECONGESTANTS
i. There is current ongoing dependence on or abuse
of a drug or substance known to have sleep- Bupropion Phenylpropanolamine
disruptive properties either during periods of use or Protriptyline Pseudoephedrine
intoxication or during periods of withdrawal. Fluoxetine
BRONCHODILATORS
ii. The patient has ongoing use of or exposure to a Citalopram
medication, food, or toxin known to have sleep- Escitalopram Theophylline
disruptive properties in susceptible individuals. Venlafaxine
iii. Insomnia is temporally associated with the substance BETA BLOCKERS STIMULANTS/ALERTING AGENTS
exposure, use, or abuse or acute withdrawal.
D. The sleep disturbance is not better explained by another Propanolol Dextroamphetamine
sleep disorder, medical or neurologic disorder, mental Pindolol Methamphetamine
disorder, medication use, or substance abuse. Metoprolol Modafinil
From American Academy of Sleep Medicine: ICSD-2 International SUBSTANCES IMMUNOSUPPRESSIVE AGENTS
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005. Caffeine Interferon
Alcohol: sleep- Prednisone
maintenance Mycophenolate
insomnia
ANTIBIOTICS/ANTIVIRALS

sleep physicians to know that they can cause nightmares
and/or sleep disturbance. Beta blockers can reduce noctur-
nal melatonin secretion. However, the mechanism by which
beta blockers disturb sleep is not known. Beta blockers that
have high lipid solubility (easily penetrate blood brain
barriere.g., propanolol) and affect norepinephrine are con-
sidered more likely to be associated with nightmares.
However, nightmares have also been noted with beta block-
ers with less lipid solubility. Beta blockers with high lipid
solubility include metoprolol, propanolol, and timolol.
Atenolol is an example of a beta blocker with lower lipid
solubility.
Effects of Alcohol Alcohol is commonly used as a sleep aid and
patients often do not connect their sleep problems with
alcohol consumption because most sleep disturbances
occur hours after the last drink.
Patients without Alcoholism Bedtime alcohol may shorten the
latency to sleep, at least on the first few nights of consump-
tion. However, bedtime alcohol consumption tends to frag-
ment sleep in the later half of the night. Alcohol also increases
the REM latency. Of interest, one study found that late after-
noon (happy hour) alcohol consumption approximately
6 hours before bedtime increased wakefulness during the
second half of sleep.36
Active Alcoholism Sleep disturbances associated with active
alcoholism include increased sleep latency, frequent awaken-
ing, and decreased subjective sleep quality. Abrupt with-
drawal of alcohol can trigger profound insomnia and marked
sleep fragmentation. A decrease stage N3 is also typically
noted. An increase in REM sleep may also occur with acute
Efavirenz (Sustiva)
Adapted from Schweitzer PK: Drugs that disturb sleep and wakefulness. In
Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep
Medicine, 4th ed. Philadelphia: Elsevier Saunders, 2005, pp. 495518.
withdrawal because alcohol suppresses REM sleep. In some
patients during acute alcohol withdrawal, sleep consists of
repeated REM episodes interposed on wakefulness.38
Abstinent Alcoholic In abstinent alcoholics (recovering alco-
holics), sleep disturbance can persist for a long period of
time with reduced stage N3 and increased wakefulness
(WASO). In one study of patients admitted to alcohol recov-
ery, an increase in REM sleep (REM sleep as % of TST) and
an increased REM density (REMs per time in REM sleep)
on admission predicted those who relapsed within 3
months.38 Another study found longer sleep latency, shorter
REM latency, and decreased stage 4 (stage N3) predicted
relapse.39
Treatment
The treatment for insomnia due to drug or substance is to
withdraw the offending agent. If a withdrawal syndrome is
possible, gradual weaning is indicated. If withdrawal of a
substance of abuse is planned, this often requires admission
to a rehabilitation or mental facility and close medical super-
vision. If chronic insomnia is present in the recovering alco-
holic or patient recovering from other drug addiction,
the use of BZRAs is not recommended for treatment. Typi-
cally, sedating antidepressants and behavioral treatments are
utilized.
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BOX 2517
Insomnia Due to Medical Condition
Diagnostic Criteria
A. Symptoms meet criteria for insomnia.
B. The insomnia is present for at least 1 month.
C. The patient has a medical or physiologic condition
known to disrupt sleep.
D. Insomnia is clearly associated with the medical
condition. The insomnia began near the time of onset of
the medical condition and waxes and wanes with
fluctuations in the severity of the medical conditions.
E. The sleep disturbance is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, medication use, or substance abuse.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Insomnia Due to Medical Condition
Many medical disorders can disturb sleep owing to associ-
ated pain (rheumatologic disorders), dyspnea or orthopnea
(cardiovascular or pulmonary disorders), nocturia (conges-
tive heart failure, diuretic use, benign prostatic hypertrophy,
untreated obstructive sleep apnea), and medication side
effects. In some patients, improved control of the medical
disorder will improve sleep. In others, the sleep disorder will
persist, especially if associated with medication side effects
(Box 2517).
Treatment
Behavioral and pharmacologic treatments may be effective if
sleep problems persist despite efforts to improve the medical
disorder. BZRAs should be used with caution in patients
with obstructive sleep apnea and chronic lung disease.
TREATMENT OF INSOMNIA
Cognitive and Behavioral Treatments
Cognitive and behavioral treatments are safe and effective
for sleep-onset and sleep-maintenance insomnia as well as
nonrestorative sleep.4046 The efficacy of behavioral treat-
ments is equal to or better than results from pharmaco-
therapy.40 Unfortunately, many locales do not have physicians,
nurses, or psychologists skilled at this form of treatment.
The 2006 update of AASM practice parameters for behav-
ioral treatment of chronic insomnia44 stated psychological
and behavioral interventions are effective and recom-
mended in the treatment of chronic primary insomnia,
secondary insomnia (due or associated to other medical
or psychiatric disorders), insomnia in older adults, and
chronic hypnotic users (Standard). Levels of evidence for
different behavioral techniques are listed in Table 256. In
2008, Clinical Guidelines for the Evaluation and Manage-
ment of Chro nic Insomnia in Adults were published.7
Chapter 25 Insomnia 497
TABLE 256
Stimulus Control Instructions
1. Lie down intending to go to sleep only when sleepy.
2. Do not use the bed for anything except sleep and sex.
Do not use the bed for reading, television watching,
eating, or worrying.
3. Do not watch the clock but if you have not fallen asleep
in 10 to 15 minutes, get out of bed and go into another
room. Stay up as long as you wish or until you feel
sleepy and then return to the bedroom.
4. If you cannot fall asleep repeat rule 3 as often as needed.
5. Get up at the same time every morning irrespective of
how much sleep you got during the night.
Goal: Help the body acquire a consistent sleep rhythm.
6. Do not nap during the day.
From Morgenthaler T, Kramer M, Alessi C, et al: Practice parameters for the
psychological and behavioral treatment of insomnia: an update. Sleep
2006;29:14151419; and Bootzin RR, Epstein D, Wood JM: Stimulus control
instructions. In Hauri P (ed): Case Studies in Insomnia. New York: Plenum,
1991, pp. 1928.
This document recommended that cognitive and behavioral
treatment be utilized as initial treatment of insomnia if
possible.
Elements of Cognitive and Behavioral Therapy
The AASM practice parameter level of evidence (Standard,
Guideline, Option) for the following techniques is listed by
the name of the technique.7,43,44 A combination of techniques
is frequently used.
Cognitive Therapy Cognitive therapy is aimed at changing the
patients belief and attitudes about insomnia.7,44 These dys-
functional cognitions are often identified using question-
naires such as the DBAS (see Appendix 251).19,20 Cognitive
therapy uses a psychotherapeutic method to reconstruct
cognitive pathways with positive and appropriate concepts
about sleep and its effects. Common cognitive distortions
that are identified and addressed in the course of treatment
include I cant sleep without medication, I have a chemical
imbalance, If I cant sleep, I should stay in bed and rest,
My life will be ruined if I cant sleep.7,20
Cognitive Behavioral Therapy of Insomnia (Standard) Cognitive
behavioral therapy (CBT) of insomnia is also sometimes
termed CBTI. This technique combines cognitive therapy
with behavioral techniques. The behavioral component may
include stimulus control therapy and/or sleep restriction
therapy with or without use of relaxation therapy. Sleep
hygiene education is often included.
Sleep Hygiene (No Recommendation) Up to 30% of patients
evaluated for insomnia have inadequate sleep hygiene.
Although education about sleep hygiene is always utilized,
there is no conclusive evidence that this alone is effective
treatment.
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498 Chapter 25 Insomnia
BOX 2518
Sleep Restriction Instructions
1. A sleep log is kept for 12 weeks to determine the mean
TST.
2. Set bedtime and wakeup time to achieve mean TST with
sleep efficiency > 85%.
The minimum TIB is 5 hr.
If TST/TIB = 0.85 then TIB = TST/0.85.
Example: If TST = 310 min, then goal for TIB = 364 (bedtime
11 PM, wake time 5:04 AM.)
3. Adjustments:
A. If TST/TIB > 0.85 for 7 days, then add 1520 min to
TIB.
B. If TST/TIB < 0.85, decrease TIB every 7 days.
Adapted from Morgenthaler T, Kramer M, Alessi C, et al: Practice parameters
for the psychological and behavioral treatment of insomnia: an update. Sleep
2006;29:14151419; and Speilman AJ, Saskin P, Thorpy MJ: Treatment of
chronic insomnia by restriction of time in bed. Sleep 1987;10:4556.
Relaxation Therapy (Standard) The term relaxation therapy
(RT) is a generic term that encompasses any number of
techniques.43,44 Progressive muscle relaxation (PMR)
focuses on somatic arousal and was developed by Edmund
Jacobsen. Thus, the technique is often called Jacobsen PMR.
In this technique, the patient systematically goes through
the parts of the body initially tensing muscles, maintaining
muscle tension, then relaxing the muscles. The patient is
asked to concentrate on the sensations associated with
tensing and then relaxation. Guided imagery relaxation
focuses on cognitive arousal and uses techniques of visual-
izing a relaxing setting or activity. RT is useful in patients
who report or display elevated levels of arousal. The tech-
nique can be helpful with both sleep-onset and sleep-
maintenance insomnia.
Stimulus Control Therapy (Standard) This is a specific type of
CBT that is based on the idea that arousal occurs as a con-
ditioned response to the stimulus of the sleep (bedroom)
environment.43,45 This technique is among the most effective
behavioral treatments. The standard instructions are listed in
Box 2518. The goal of stimulus control therapy (SCT) is to
extinguish the negative association between the bed and
undesirable outcomes such as wakefulness, frustration, and
worry. These associations become conditioned as a result of
prolonged efforts to fall asleep and time in bed awake. SCT
will replace these negative associations with positive associa-
tions between the bed and sleep.
Sleep Restriction Therapy (Guideline) Sleep restriction therapy
(SRT; Box 2519) limits the time in bed to the TST as derived
from sleep logs.46 The goal is to improve sleep continuity,
enhancing sleep drive with sleep restriction. Sleep will
become more consolidated when long periods in bed and
napping are prohibited. As sleep continuity improves, the
BOX 2519
GABAA Receptor and Subunits
GABAA RECEPTOR COMPLEX
Five subunits: two alpha, two beta, one gamma subunits
BZ receptor: between alpha and gamma subunits
GABA receptor: between alpha and beta subunits
Barbiturate receptor
SUBUNITS
Alpha (1, 2, 3, 4, 5, 6)
Beta (1, 2, 3, 4)
Gamma (1, 2, 3)
Delta ()
Epislon ()
Pi ()
Rho (1, 2, 3)
Most common GABAA receptor is (1, 2, 2) (understood
to mean 2 1, 2 2, 1 2)
BZ = benzodiazepine; GABA = gamma-aminobutyric acid.
time in bed is gradually increased. When using this tech-
nique, the patient should be cautioned about sleepiness to
prevent accidents or other mishaps.
Paradoxical Intention (Guideline) Instructing the patient to pas-
sively remain awake and avoid any effort (intention) to fall
asleep. The goal is to eliminate performance anxiety.
Biofeedback (Guideline) Biofeedback trains the patient to
control some physiologic variable through visible or auditory
feedback. The goal is to reduce somatic arousal.
Multicomponent Therapy (Without Cognitive Therapy) (Guide-
line) This form of treatment uses multiple behavioral tech-
niques (e.g., SCT, SRT, RT) without cognitive therapy (Table
257).
Evidence for Behavioral Treatment
CBTI for periods of 4 to 8 weeks has been proven effective
by randomized, controlled trials comparing CBT with stan-
dard care or pharmacotherapy. In contrast to pharmaco-
therapy, the benefits persist when treatment is stopped.
Jacobs and colleagues47 compared CBT, pharmacotherapy
(zolpidem 10 mg nightly 28 days then 5 mg nightly for 7
days, then 5 mg every other day for 7 days), combined
therapy (zolpidem + CBT), or placebo over 6 weeks of active
treatment and another 2 weeks of either drug washout or
consolidation of CBT (no treatment sessions). The main
outcome was the sleep-onset latency assessed by diary. The
greatest improvement was with CBT and there was no
advantage to combined treatment. In addition, at follow-up,
benefits of CBT were maintained (Fig. 255). Edinger and
associates48 compared CBT with RT and quasidesensitization
(placebo). The CBT group had a 54% reduction in WASO
compared with 16% with relaxation and 12% with placebo.
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 Chapter 25 Insomnia 499

60
Midtreatment Smith and coworkers49 compared the effect sizes of CBT and
pharmacotherapy with respect to sleep latency, TST, and
Changes in sleep latency, %
After treatment
50
WASO and found CBT to be equal or better. Figure 256
40 illustrates the time course of improvement in TST with
temazepam and CBT from a study by Morin and colleagues.50
30 The major point is that, unlike pharmacotherapy, improve-
20
ment with CBT continues after the active treatment period.
In summary, CBT is effective for measures of sleep-onset
10 insomnia, sleep-maintenance insomnia, and nonrestor-
ative sleep. There is currently no evidence that adding
0
CBT Combination Pharmacotherapy Placebo hypnotics (combined treatment) has any advantage.
therapy
Treatment condition CBT in Hypnotic-Dependent Patients and
FIGURE 255 Percent changes (decreases) in the sleep latency with the four treatment in Co-morbid Insomnia
conditions. Combination therapy included a combination of cognitive behavioral Although studies to date have not documented an advantage
therapy (CBT) and pharmacotherapy. CBT was more effective than pharmacotherapy of combining CBT and hypnotics, CBT can be used in
(P = .03) and placebo (P = .02). Combination therapy was more effective than patients already on hypnotics with the possible goal of
pharmacotherapy (P = .02) or placebo (P = .001). Combination therapy and CBT therapy weaning the hypnotics.
did not differ. From Jacobs GD, Pace-Schott EF, Stickgold R, Otto MW: Cognitive behavior Several studies have documented the efficacy of CBT in
therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct patients on hypnotics.5153 Using structured programs, hyp-
comparison. Arch Intern Med 2004;164:18881896.
notic tapering and withdrawal is facilitated by combining the
process with CBTI.5153 In one study comparing supervised
benzodiazepine (BZ) withdrawal, CBT alone, or supervised

TEMAZEPAM (TEM) VS. CBT IN THE TREATMENT FIGURE 256 Total sleep time (TST) in groups treated with temazepam
OF PRIMARY INSOMNIA (TEM) and cognitive behavioral treatment (CBT). Note that after 8 weeks of
TST
treatment with TEM, the benefits decreased (drug stopped after 8 wk).
395 However, the CBT group continued to show improvement. From Riemann
CBT D, Perlis ML: The treatments of chronic insomnia: a review of benzodiazepine
385
receptor agonists and psychological and behavioral therapies. Sleep Med Rev
375
2009;13:205214, data from Morin CM, Colecchi C, Stone J, et al: Behavioral
365 and pharmacological therapies for late life insomnia: a randomized controlled
355 trial. JAMA 1999;281:991999.
TEM
345
335
325
315
Baseline 8 weeks of Follow up Follow up Follow up
therapy (3 months) (12 months) (24 months)

TABLE 257
Evidence Levels Concerning Behavioral Techniques for Treatment of Insomnia
EFFECTIVE (STANDARD) EFFECTIVE (GUIDELINE) NO RECOMMENDATION
Cognitive-behavioral treatment (with Paradoxical intention Improved sleep hygiene
or without relaxation therapy)
Stimulus control therapy Biofeedback
Relaxation therapy Sleep restriction
Multicomponent therapy (combinations of
SCT, RT, and SRT without cognitive therapy)
RT = relaxation therapy; SCT = stimulus control therapy; SRT = sleep restriction therapy.
From Morgenthaler T, Kramer M, Alessi C, et al: Practice parameters for the psychological and behavioral treatment of insomnia: an update. Sleep 2006;29:14151419.
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500 Chapter 25 Insomnia
withdrawal and CBT, all groups significantly reduced BZ use.
However, more patients were BZ free in the combined group
and both groups with CBT had better improvements in sub-
jective sleep quality.51 The utility of CBT is not confined to
primary insomnia. CBT has also proved effective in second-
ary (co-morbid) insomnia due to mental or medical disor-
ders.53 Whereas it is appropriate to optimize treatment of the
underlying co-morbid disorder, physicians should remem-
ber that CBT as well as hypnotics may improve insomnia
complaints.
Pharmacologic Treatment of Insomnia
GABABZChloride Ionophore Complex
GABA is the major inhibitory neurotransmitter in the central
nervous system. There are two major GABA receptor sub-
types GABAA and GABAB. The GABAA receptor is associated
with a chloride (Cl) channel ionophore located in cell mem-
branes. Ionophores are molecular complexes located in cel-
lular lipid membranes that allow transport/passage of
compounds across the membrane. The GABAA receptor is
the binding site for several drugs other than GABA including
agonists (muscimol, gaboxadol) and antagonists (bicucul-
line). The GABAA receptor complex also contains a receptor
for BZs and related compounds, hence, the complex is
usually referred to as the GABAbenzodiazepinechloride
ionophore complex (GBC).5456 When GABA binds the
GABAA receptor on the complex, this allows passage of chlo-
ride ions through the membrane, resulting in hyperpolariza-
tion and reduced neuronal activity. When BZs and certain
nonbenzodiazepine medications bind the BZ receptor on the
GBC, the configuration of the GABA receptor changes to
enhance the ability of GABA binding to open the associ-
ated chloride channel (increased frequency). The medica-
tions are, therefore, sometimes called GABAA receptor
modulators. Medications (including nonbenzodiazepines)
that bind the BZ receptor and enhance the ability for GABA
to open the chloride channel are called benzodiazepine
receptor agonists (BZRAs).
The GBC is composed of five protein subunits surround-
ing the chloride channel (Fig. 257). The subunits compos-
ing the GBC have different structure and are denoted as
alpha, beta, gamma, epsilon, and rho (see Box 2519).54,55
The receptor complex is composed of two alpha, two beta,
FIGURE 257 Left, A schematic representation of the
GABAAbenzodiazepinechloride ionophore complex with five
subunits arranged around the chloride pore. Right, A view
from overhead shows the location of the GABAA receptors at the
junction of the 1 and 2 subunits and the benzodiazepine
receptor at the junction of the 1 and 2 subunits.
and one gamma subunit. In addition, the alpha, beta, and
gamma subunits have isoforms (e.g., 1, 2, 3, ). The
GABA binding site is located between alpha and beta sub-
units and the BZ receptor site is located between alpha and
gamma subunits (see Fig. 257). The most common GBC
receptor configuration is denoted as 1, 2, 2 (understood
to mean two 1, two 2, and one 2 subunits) also known as
a BZ type 1 receptor. The GBC also has receptors for barbi-
turates, certain inhaled anesthetics, and alcohol.
GABAA receptors composed of different alpha subtypes
are located in different locations of the central nervous
system and mediate different effects (see Box 2519). GABAA
receptors composed of 1 subunits mediate sedation (hyp-
notic effect), amnesia, and anticonvulsant effects. GABAA
receptors associated with 2 and 3 subunits mediate anxio-
lytic and myorelaxant effects.
BZs tend to have high affinity for all these subtypes. The
new nonbenzodiazepine BZRAs (zolpidem, zaleplon, eszopi-
clone), also known as the Z hypnotics, have preferential
binding to GABAA receptors containing certain subunits.
Zolpidem and zaleplon selectively bind GABAA receptors
containing 1 subunits and are often called selective BZRAs
(Table 258). However, the preferential binding is only rela-
tive, and at higher doses, GABAA receptors containing 1, 2,
and 3 are bound. Eszopiclone has receptor binding more
like traditional BZs but has many of the same advantages of
the other Z hypnotics. Eszopiclone does bind 1 subunits
with higher affinity than 3 but also binds 2 subunit recep-
tors with only slightly lower affinity than 1 subunits.56 The
clinical importance of selective binding for the clinical effects
TABLE 258
Relative Binding of Benzodiazepine
Receptor Subtypes
ALPHA 1 ALPHA 2 ALPHA 3 ALPHA 5
Zaleplon 17 2 2 1
Zolpidem 21 1 1 Negligible
Eszopiclone 8 5 1 8
1 = the lowest affinity of a given drug for any receptor.
Adapted from Nutt DJ, Stahl SM: Searching for perfect sleep: the continuing
evolution of GABAA receptor modulators as hypnotics. J Psychopharmacol
2010;14:16011612; Epub 2009;November 26.
Cl
2
Benzodiazepine
2 receptor
Cl 1
pore
1 2
Membrane
GABAA
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 Chapter 25 Insomnia 501

TABLE 259
GABAA Receptor Alpha Subunits and Associated Actions
PROPORTION OF
ACTION GABA RECEPTORS LOCATION
1 Sedative, amnestic, 60% All brain regions
anticonvulsant Cortex, hippocampus
2 Anxiolytic, myorelaxant 1520% Cortex, hippocampus, amygdala, forebrain, hypothalamus
3 Anxiolytic, myorelaxant 1015% Cerebral cortex, thalamus (reticular nucleus)
4, 6 Insensitive to BZ Dentate gyrus
5 High affinity for BZ Cerebral cortex, hippocampus
Low affinity for zolpidem
BZ tolerance
BZ = benzodiazepine; GABA = gamma-aminobutyric acid.

of the Z hypnotics remains uncertain. In addition, the ulti- TABLE 2510

mate effect of a BZRA depends not just on receptor affinity Effects of Benzodiazepine Receptor Agonists
but also on the potency of the medication and the achievable ACTIONS
drug concentration.
Traditionally, the sedation effects of BZRAs was equated Hypnotic
Amnestic
with hypnotic action. However, new information is available
Anxiolytic
from studies in genetically manipulated mice.5557 As each of Myorelaxant
the subunits on the GABAA receptor is associated with a Anticonvulsant
single gene, genetic manipulation (knock-out, knock-in
mice) allows the importance of subunits to be assessed.56 SIDE EFFECTS
These studies suggest GABAA receptors containing 2 and 3 Sedation
subunits, although not associated with sedation, are involved Anterograde amnesia (learning new material)
with the control of manifestations of sleep. For example, BZs Ataxia, falls
can induce sleep in 1 knock-out mice. One study suggests Sleepwalking, sleep violence, sleep-related eating disorder
that GABAA receptors with 2 subunits were responsible for Respiratory depression
Tolerance
generating delta waves during nonrapid eye movement
Dependence, abuse
(NREM) sleep.57 GABAA receptors with 3 subunits are
Rebound insomnia (especially triazolam)
present in the reticular nucleus of the thalamusan area
responsible for thalamic-cortical oscillations (sleep spin-
dles).56 In the future, the importance of GABAA receptors
associated with 2 and 3 subunits for the control of sleep
will be better defined (Table 259).
TABLE 2511
BZRA Effects and Side Effects The BZRAs have a number of Effects of Benzodiazepine Receptor Agonists
important clinical effects including sedation (hypnotic), on Sleep
amnestic, anxiolytic, myorelaxant, and anticonvulsant (Table Improved sleep continuity
2510). As noted previously, zolpidem and zaleplon bind Decreased sleep latency (short- and intermediate-acting
preferentially to BZ receptor-associated 1 subunits and, BZRAs)
therefore, have less anxiolytic and myorelaxant activity Increased total sleep time (intermediate-acting BZRAs)
than the classic BZs. However, eszopiclone appears to have Decreased wake after sleep onset (intermediate-acting
more affinity for 2 units than zolpidem and zaleplon and, BZRAs)
therefore, possibly more anxiolytic effects. All three Z drugs Decreased stage N3
are associated with less reduction in stage N3 than classic Reduced amplitude of slow waves (less with alpha
BZs (mainly due to less reduction in slow wave amplitude) 1-selective BZRAs)
as well as less rebound insomnia or evidence of tolerance Increased sleep spindles and faster activity
(decreased effect at the same dose).58,59 Zaleplon has a very
Decrease in REM sleep: mild, less with alpha 1-selective
short duration of action (Table 2511) and may have less drugs
residual sedative effects especially after middle of the night
BZRAs = benzodiazepine receptor agonists; REM = rapid eye movement.
dosing.5861 Zolpidem has a longer half-life than zaleplon but
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502 Chapter 25 Insomnia
shorter than eszopiclone. Zolpidem may not increase TST in
some patients, and for this reason, zolpidem CR (continuous
release) was developed. Zolpidem CR is a coated two-layer
tablet with one layer that releases the drug content immedi-
ately and another layer that slowly releases additional drug
beyond three hours after administration. Zolpidem CR,
eszopiclone, and temazepam have intermediate durations of
action (Table 2512) and may be more effective for sleep-
maintenance insomnia than medications with a shorter
duration of action. However, patients are quite variable in
their response to the different hypnotics, and some patients
with sleep-maintenance insomnia will respond to generic
zolpidem.
The BZRAs have a number of effects on sleep (see Table
2511). A decrease in sleep latency is common to all medica-
tions. Those with an intermediate or longer duration of
action also can increase TST and decrease WASO. BZRAs
can increase sleep spindle activity and higher EEG frequen-
cies. The BZs reduce stage N3 sleep with no or a mild reduc-
tion in REM sleep. The major effect on stage N3 sleep is via
a reduction in slow wave amplitude. As mentioned previ-
ously, the nonbenzodiazepine BZRAs (Z hypnotics) result in
no or minimal decrease in the amount of stage N3 because
they do not substantially reduce the amplitude of slow waves.
The clinical importance of less reduction in stage N3 sleep is
still unclear.
The BZRAs have a number of side effects (see Table 2510)
including anterograde amnesia (decreased ability to learn and
retain new information), ataxia (fall risk), as well as residual
sedation during the day. Of note, eszopiclone is associated
with an unpleasant (often metallic) taste in a significant
number of patients (25%).62,63 BZRAs can also be associated
with nausea in some patients. They are not recommended for
use in nursing women or in pregnant women. In 2007, the
U.S. Food and Drug Administration (FDA) required packag-
ing information on the BZRA hypnotics to include a warning
regarding several specific potential adverse effects. The new
information states that BZRAs have been associated with
sleep behaviors including sleepwalking, eating, driving,
and sexual behavior. Patients taking BZRAs should allow
for adequate sleep time and NOT take BZRAs in combina-
tion with other sedatives, alcohol, or sleep restriction. Zol-
pidem is the BZRA most often associated with sleepwalking
and the sleep-related eating disorder, but these manifestations
can happen with the other BZRAs. Residual sedation is
another important side effect of BZRAs. In general, shorter-
acting medications are less likely to cause residual seda-
tion.60,61 Respiratory depression due to the BZRAs hypnotics
is uncommon. However, caution is advised with the use of
hypnotics in patients with hypoventilation, obstructive sleep
apnea, and severe lung disease. Respiratory depression is
more likely when BZRAs are combined with other central
nervous system depressants such as alcohol or narcotics.
The potential for dependence and abuse resulted in the
BZRA hypnotics being classified as Schedule 2 medications.
Drugs with high receptor binding affinity such as lorazepam,
midazolam, and triazolam cause more side effects with
withdrawal.58 Triazolam causes rebound insomnia and is no
longer recommended as a first-line hypnotic. Significant
rebound insomnia has NOT been noted in most studies of
zaleplon, zolpidem, and eszopiclone.58,59,62 However, with-
drawal side effects and rebound insomnia can potentially
occur with all BZRAs and slow withdrawal is recommended
if possible.
General Considerations for BZRA Hypnotic Use BZRA hypnotics
are well studied and the medications listed in Table 2512
are FDA approved for treatment of insomnia unless other-
wise noted. It is especially important to note the duration of
action. The hypnotics are grouped into nonbenzodiazepines
and BZs. At this time, the only nonbenzodiazepine available
in the United States in generic form is zolpidem. The brand
name Z hypnotics are in general quite expensive. Some
general considerations for using hypnotics and choosing a
specific hypnotic medication are listed in Table 2513.
Ideally, hypnotics should be used on a short term or inter-
mittent basis at the lowest effective dose. A lower dose and
more caution is indicated in the elderly or in patients with
impaired hepatic function because most BZRAs undergo
hepatic metabolism.7,56 Until 2005, the FDA labeling stated
that the hypnotic medications were indicated for short-term
use. Since 2005, the duration of action has not been specified.
New studies have documented effectiveness of some medica-
tions for 6 months or longer6366 (Table 2514). Clinical
experience also has noted continued long-term effectiveness
(at least by patient report) in a number of BZRA hypnotics.
The effect of eszopiclone on sleep latency for a 12-month
period (blinded and open-label portions) is illustrated in
Figure 258.
75
PBO-ESZ
ESZ-ESZ
60
Minutes (median)
45
30 * * *
15
0
Base 1 2 3 4 5 6 7 8 9 10 11 12
Month of study
Double-blind period Open-label period
FIGURE 258 The continued effect of eszopiclone on sleep latency over a 12-month
study. Double-blind and open-label periods are shown. The squares (ESZ-ESZ) show
patients who used 3 mg of eszopiclone for the entire period. The diamonds (PBO-ESZ)
show patients originally on placebo but converted to eszopiclone for the last 6 months.
Statistical comparisons made against PBO-ESZ and ESZ-ESZ values at 6 months.
* = P < .05 ESZ-ESZ during open-label period vs. 6-month ESZ-ESZ value. = P < .0001
PBO-ESZ group in open-label period vs. 6 month PBO-ESZ value. From Roth T, Walsh JK,
Krystal A, et al: An evaluation of the efficacy and safety of eszopiclone over 12 months in
DaneshGroup.com
patients with chronic primary insomnia. Sleep Med 2005;6:487495.
TABLE 2512
Commonly Used Benzodiazepine Receptor Agonist and Melatonin Receptor Agonist Hypnotic Medications
BENZODIAZEPINE RECEPTOR AGONISTS USED AS HYPNOTICS (SCHEDULE IV CONTROLLED SUBSTANCES)
NONBENZODIAZEPINES
ONSET
GENERIC (BRAND MEDICATION OF DURATION OF SELECTED SIDE EFFECTS
NAME) FORMS DOSE ACTION ACTION INDICATIONS AND COMMENTS
Zaleplon 5, 10 mg 10 mg qhs, max 20 mg 1020 min Short-acting SOI Rescue medication if 4 hr
(Sonata) capsule 5 mg hs in elderly, (T1/2 = 1 hr) left for sleep
Pyrazolopyrimidine debilitated, mild to
moderate hepatic
impairment, or
concomitant
cimetidine
Zolpidem generic 5, 10 mg 10 mg hs, max 10 mg 1020 min Short- to SOI, SMI Generic available in
imidazopyridine tablets 5 mg in elderly, intermediate- United States
debilitated, hepatic acting Sleep-related eating
impairment T1/2 2.5 (1.54) hr disorder and
sleepwalking reported
Zopidem CR 6.25, 12.5 mg 6.2512.5 mg qhs 1020 min Controlled-release, SOI, SMI Swallow whole not
(Ambien CR) tablets 6.25 mg qhs in elderly intermediate- crushed, cut, or chewed
imidazopyridine acting
T1/2 3 hr*
Eszopiclone 1, 2, 3 mg 23 mg qhs (max 3 mg) 1030 min Intermediate- SOI, SMI Unpleasant taste
(Lunesta) tablets 1 mg qhs in elderly and acting common side effect
Cyclopyrrolones hepatic impairment T1/2 6 hr
(max 2 mg)
BENZODIAZEPINES
Triazolam 0.125 mg 0.1250.25 mg qhs 1020 min Short acting SOI Rebound insomnianot
(Halcion) 0.25 mg 0.125 in elderly T1/2 25 hr a first-line hypnotic
Estazolam 1, 2 mg 12 mg hs 1530 min Intermediate- SOI, SMI Residual daytime
(ProSom) tablets 0.5 mg in elderly, acting sleepiness can occur
debilitated T1/2 824 hr
Temazepam 7.5, 15, 30 mg 1530 hs 4560 min Intermediate- SOI, SMI Delayed onset of action
(Restoril) capsules 15 mg in elderly, acting
debilitated T1/2 820 hr
Flurazepam 15, 30 mg 1530 mg hs 1530 min Long-acting SMI Residual daytime
(Dalmane) capsule 15 mg hs in elderly, T1/2 47100 hr sleepiness active
debilitated metabolites
BENZODIAZEPINES NOT FDA APPROVED AS HYPNOTICS
Clonazepam 0.5, 1.0, 0.250.5 mg qhs Peak Long-acting SMI Residual daytime
(Klonopin) 2.0 mg levels T1/2 1850 hr sleepiness
13 hr Potent BZRA
Not FDA approved as
hypnotic
Lorazepam 0.5, 1.0 mg 0.51.0 mg qhs Peak Long-acting Not FDA approved as
(Ativan) 24 mg levels T1/2 14 hr hypnotic
13 hr Wean slowly, can cause
withdrawal side effects
MELATONIN RECEPTOR AGONISTS (NOT SCHEDULE IV)
Ramelteon 8 mg tablet 8 mg hs 2030 min T1/2 12.6 hr SOI No addiction/dependence
Rozerem Active metabolite potential use with
MII is 25 hours Luvox contraindicated
(but 20 X less Do not use with hepatic
potent) impairment

zolpidem designed to improve sleep maintenance. Funda Clin Pharmacol 2006;20:397403. DaneshGroup.com
*Time when drug concentration reaches 50% of maximum = 4.6 hours. Weinling E, McDougall S, Andre F, et al: Pharmacokinetic profile of a new modified release formulation of

BZRA = benzodiazepine receptor agonist; FDA = U.S. Food and Drug Administration. SMI = sleep-maintenance insomnia; SOI = sleep-onset insomnia.
504 Chapter 25 Insomnia

TABLE 2513 Choice of BZRA Hypnotic Medication The major characteristic of

General Recommendations for Benzodiazepine BZRA medications to consider in choosing a hypnotic (see
Receptor Agonist Hypnotic Treatment and Choice Table 2513) is the duration of action.7,58 Short-acting med-
of Medication ications work for sleep-onset insomnia but may not help
GENERAL CONSIDERATIONS
with sleep-maintenance insomnia. Triazolam has a short
duration of action but is associated with significant rebound
1. Use lowest dose for the shortest time possible. insomnia and is no longer considered a first-line agent for
2. Take BZRAs on an empty stomach. insomnia. Zaleplon has a very short duration of action and
3. BZRAs are not recommended in nursing or pregnant
may be useful as a rescue medication for middle of the
women.
night dosing (as long as 46 hr of potential sleep remain).60,61
4. Rapid reduction in dose or withdrawal can cause
withdrawal symptoms including rebound insomnia. One study of experimental awakening during the middle of
5. Use with caution in patients with OSA and lung disease the night found morning effects with zolpidem but not with
(COPD). zaleplon.61 Zolpidem has a short to intermediate action and
6. Do not combine with alcohol; use caution with other may work for some but not all patients as treatment of sleep-
sedatives. maintenance insomnia.
CONSIDERATIONS IN CHOICE OF HYPNOTIC Intermediate-acting medications are indicated for sleep-
onset and sleep-maintenance insomnia but may cause
1. Symptom pattern (SOI, SMI, both) and BZRA duration of daytime sedation in some patients. Temazepam, eszopiclone,
action.
and zolpidem CR are in this category. Of note, temazepam
2. Treatment goals.
has a fairly long onset of action in many patients (see Table
3. Past treatment (failures, side effects).
4. Patient preferences. 2512) and may not be effective for sleep onset insomnia in
5. Cost (generic much cheaper). some patients. The duration of action of zolpidem CR is 46
6. Availability (e.g., covered by health plan). hours but eszopiclone may be more effective for sleep main-
7. Co-morbid conditions tenance insomnia in some patients. On the other hand, zol-
8. Avoid BZRA if history of medication dependence, pidem CR may cause less residual sedation in the morning.
alcoholism. Long-acting medications have an increased risk of
9. Medication interactions daytime sedation and other residual effects. Flurazepam also
10. Combination of fluvoxamine and ramelteon has active metabolites. It is important to note that sometimes
contraindicated. patients who fail to respond to a given BZRA will respond
11. Side effects (e.g., anticholinergic in patients with benign
to an alternate BZRA. Lorzepam (Ativan) and clonazepam
prostatic hypertrophy).
are two BZ BZRAs that are not FDA approved for primary
BZRA = benzodiazepine receptor agonist; COPD = chronic obstructive
pulmonary disease; OSA = obstructive sleep apnea; SMI = sleep-maintenance
insomnia. Lorazepam is approved for treatment of anxiety
insomnia; SOI = sleep-onset insomnia. and may work better than approved hypnotics if insomnia is
due to anxiety. Although the standard dose for anxiety is 2
to 4 mg, lower doses (0.51 mg) may work as a hypnotic. The
medication has a relatively long half-life and withdrawal

TABLE 2514
Studies Documenting Long-term Effectiveness of Benzodiazepine Receptor Agonists
TYPE OF STUDY
BRZA STUDY FOCUS (LENGTH) COMMENTS STUDY
Eszopiclone Adults RCT-DB-PC Efficacy maintained for 6 mo including sleep latency Krystal,
3 mg Chronic insomnia 6 mo and ability to function during the day 200363
Eszopiclone Adults 12 mo total (6-mo 6 mo DB placebo (no benefit) changed to open-label Roth,
3 mg Chronic insomnia open-label eszopiclone showed benefit over the last 6 mo 200564
extension) DB eszopiclone benefits were sustained over 12 mo
Eszopiclone Older adults primary RCT-DB-PC Efficacy maintained Ancoli-
2 mg and co-morbid 12-wk treatment No rebound Israel,
insomnia 2-wk withdrawal (SB) 201065
Zolpidem-ER Chronic primary RCT-DB-PC 37 nights/wk efficacy maintained Krystal,
12.5 mg insomnia 24 wk (6 mo) Sleep onset and sleep maintenance improved 200866
Next day concentration improved
Morning sleepiness improved
DB = double-blind; PC = placebo-controlled; RCT = randomized, controlled trial; SB = single-blind.
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 Chapter 25 Insomnia 505

symptoms may occur after long-term use. Clonazepam is a
potent BZRA with a very long half-life and is commonly
associated with morning grogginess. However, individual
patients may respond well to this medication and not report
morning sedation. Starting with the lowest possible dose and
having patients plan on a long sleep period is prudent. An
occasional rare patient requires up to 2 mg of clonazepam
for sleep-maintenance insomnia.
Several studies have compared continuous versus inter-
mittent use of hypnotics and found intermittent hypnotic
administration was effective. Walsh and associates67 com-
pared zolpidem 10 mg (more than 3 but no more than 5
nights per week on as-needed basis) versus placebo and
found significant benefits. Hajak and coworkers68 compared
nightly zolpidem, placebo twice weekly, and zolpidem 5
nights per week and found both zolpidem regimens were
effective compared with placebo.
Ramelteon (Rozerem)A Melatonin Receptor Agonist
Ramelteon is the first melatonin receptor agonist approved
in the United States for treatment of insomnia.6972 It is an
MT1/MT2 receptor agonist. The effects at MT1 are thought
to inhibit neuronal firing of the suprachiasmatic nucleus
(SCN), effectively turning off the alerting signal and allowing
sleep to occur. In contrast, MT2 receptor effects are thought
to mediate melatonins phase shifting effects on circadian
rhythms. Ramelteon is about 17 times more potent at the
MT1/MT2 receptors than melatonin. Studies have shown an
absence of next-day residual effects, withdrawal, or rebound
effects. The medication lacks abuse potential. Randomized,
placebo-controlled studies have demonstrated efficacy of
ramelteon with most effects being on sleep latency. The med-
ication has a short half-life. One study by Mayer and col-
leagues71 demonstrated that 8 mg of ramelteon 30 minutes
before bedtime reduced subjective sleep latency over a
6-month trial. Ramelteon also decreased latency to persis-
tent sleep by PSG over the trial. TST was increased only at
week 1. Side effects of ramelteon include headache, nausea,
dizziness, somnolence, nightmares, hallucinations, and
uncommonly suicidal ideation. Arthralgia and myalgia can
also occur. Because ramelteon has no dependence potential,
it may be a good choice for patients with alcohol or drug
dependency. Ramelteon undergoes hepatic metabolism and
should be avoided in patients with severe liver disease. Use
of ramelteon is contraindicated in patients taking luvox-
amine, because this antidepressant significantly increases the
levels of ramelteon in the blood.7
Sedating Antidepressants and Antipsychotics
Sedating antidepressants used in doses lower than required
for antidepressant effects are widely used as hypnotics
(Table 2515). Until recently, relatively little evidence has

TABLE 2515
Sedating Antidepressants and Antipsychotics Used Off-Label As Hypnotics (Not FDA Approved
As Hypnotics Except for Silenor)
NAME GENERIC DOSE HYPNOTIC
(BRAND NAME) FORMS DOSE COMMENTS NOTABLE SIDE EFFECTS
Trazodone 50, 100 mg 25100 mg qhs Less anticholinergic side Priapism
effects than TCAs Postural hypotension
T1/2 9 (314) hr
Mirtazapine 15, 30 mg 7.515 mg qhs T1/2 2040 hr Weight gain
(Remeron) Higher doses less sedating
TCAs
Amitryptyline 10, 25, 1025 mg qhs T1/2 1026 hr metabolite Dry mouth, constipation
(Elavil) 50 mg active (nortriptyline) QT prolongation
Doxepin 10, 25, 50 110 mg (elixir) T1/2 68 hr Dry mouth, constipation
(Sinequan) 10 mg/mL 25 mg qhs
Doxepin 3, 6 mg 6 mg qhs T1/2 68 hr FDA approved for sleep-maintenance insomnia
(Silenor) 3 mg qhs Cimetidine increases drug levelsmax dose of
elderly doxepin should not exceed 3 mg if cimetidine
co-administered
Sertraline can also increase levels of doxepin
SEDATING ANTIPSYCHOTIC MEDICATIONS
Quetiapine 25, 50, 100 12.550 mg T1/2 6 hr Weight gain, headache, dizziness
(Seroquel) qhs Intermediate-acting Neuroleptic syndrome
Tardive dyskinesia
Long QT
Lens change
FDA = U.S. Food and Drug Administration; TCAs = tricyclic antidepressants.
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506 Chapter 25 Insomnia
demonstrated their effectiveness as hypnotics in patients
without depression. Trazodone is a sedating antidepressant
with minimal anticholinergic activity that is frequently used
as a hypnotic. The evidence for its efficacy as a hypnotic in
patients without depression is very modest.73,74 However,
some patients seem to benefit from the medication. It is a
reasonable hypnotic in co-morbid depression,75,76 in patients
with significant sleep apnea, or in patients with a history of
medication dependence. Its main side effects are priapism
and postural hypotension. The usual dose is 25 to 100 mg
qhs. Mirtazapine (Remeron) is used in low doses as a hyp-
notic.77 Of interest, lower doses (7.5 mg and 15 mg) are
sometimes more sedating than higher doses. The major side
effect is weight gain. Mirtazapine antagonizes alpha 2 recep-
tors and serotonin (5HT2) receptors. Its sedation is believed
due to its antihistamine activity. Doxepin (Sinequan, Silenor)
and amitriptyline (Elavil) are sedating tricyclic antidepres-
sants that have been used in low doses as hypnotics. They
have significant anticholinergic side effects (dry mouth, con-
stipation, urinary retention). It is important to recall that
tricyclic antidepressants are very dangerous in overdose.
Recently, doxepin has been evaluated with randomized, con-
trolled trials for its utility as a hypnotic in low doses (1, 3,
6 mg). Lower doses avoid significant anticholinergic side
effects.78 In these studies, the major significant effect was a
decrease in WASO. The mechanism of hypnotic action of
doxepin is antagonism of histamine (H1) receptors. A prepa-
ration of doxepin (Silenor) available as 3-mg and 6-mg
tablets has recently been approved by the FDA for treatment
of sleep-maintenance insomnia. This is the only sedating
antidepressant FDA approved for treatment of insomnia.
Silenor is fairly expensive. An alternative is to use a low dose
of generic doxepin (10 mg or 5 mg using the elixir). Medica-
tions with substantial anticholinergic activity can cause
urinary retention in patients with benign prostatic hypertro-
phy. Use of even low-dose doxepin in patients with severe
urinary retention should be avoided.
Quetiapine (Seroquel) is a second-generation antipsy-
chotic medication that antagonizes histamine, dopamine D2,
and 5HT2 receptors. At low doses, the medications main
effect is as an antihistamine. Quetiapine is indicated for treat-
ment of schizophrenia and bipolar disorder. Side effects
include QT prolongation, weight gain, extrapyramidal symp-
toms, headache, lens changes/cataracts, and decreased white
blood cell count. Even at low doses, quetiapine has been asso-
ciated with significant weight gain. Due to its side effects, this
medication is usually not used in patients without significant
psychiatric disorders unless other treatments have failed.
Other Medications Used for Insomnia
Other sedating medications have been used for insomnia.
Gabapentin (an anticonvulsant structural analog of GABA)
is used for chronic pain and the restless legs syndrome. The
half-life of gabapentin is approximately 5 to 9 hours, and it
is excreted by the kidneys unchanged. Due to the sedative
properties of gabapentin, the medication can be used as a
hypnotic treatment alternative in patients who do not
respond to or tolerate other medications. The usual dose is
300 to 900 mg at bedtime. Side effects include dizziness,
ataxia, and less commonly, leukopenia. Gabapentin could
potentially be useful in patients with insomnia associated
with pain. The use of melatonin has been analyzed with a
meta-analysis and appears to have a small effect on sleep
latency with little effect on WASO or TST.79 One problem
with both ramelteon and melatonin as hypnotics is that the
endogenous melatonin levels are already elevated during the
dark hours. The hypnotic dose is 3 to 5 mg. There is some
evidence that valerian extracts have some benefit as a hyp-
notic.80 Antihistamines (diphenhydramine and doxylamine)
are the primary ingredients in over-the-counter sleep aids.
There is some limited evidence for their efficacy.80 The main
problem is that they have considerable anticholinergic activ-
ity (urinary retention) and can cause daytime sedation.7
Pharmacotherapy for Co-morbid Insomnia
of Psychiatric Disorders or in Patients
with Dependence Issues
Patients with anxiety or major depressive disorders fre-
quently have prominent co-morbid insomnia. In such
patients, one might choose to use (1) a sedating antidepres-
sant at antidepressant doses (e.g., mirtazapine 3045 mg
qhs), (2) the combination of an effective nonsedating anti-
depressant (at antidepressant doses) and a sedating antide-
pressant at low doses, or (3) the combination of an effective
nonsedating antidepressant + BZRA hypnotic. Fava and
associates81 studied a group of patients with both major
depressive disorder and insomnia. The combination of
fluoxetine (FLX) and placebo was compared with FLX +
3 mg of eszopiclone. Co-administration of eszopiclone
resulted in improved subjective sleep latency, WASO, and
TST compared with FLX alone. Whereas this result was not
unexpected, a surprising finding was that there was also
greater improvement in depression at 4 and 8 weeks with
the combination of FLX and eszopiclone. A similar trial
with zolpidem found improvement in sleep but no evidence
of greater improvement in depression.82 It is possible eszopi-
clone has beneficial antidepressant effects not present with
zolpidem. Indeed, eszopiclone does have greater binding
affinity for BZ receptors associated with 2 subunits that
have an effect on mood. However, a definite benefit of eszop-
iclone over zolpidem remains to be documented by studies
comparing the drugs in a head-to-head comparison in
depressed patients. In another study, the use of zolpidem
when added to escitalopram (Lexapro) did improve sleep
but not anxiety in a group of patients with generalized
anxiety disorder.83 In summary, BZRAs can be used effec-
tively in combination with antidepressants in patients with
depression or anxiety associated with prominent insomnia
complaints. In patients with a history of past or current
alcohol or BZ dependence, the use of BZRAs is problem-
atic. For these patients, use of ramelteon (no abuse poten-
tial) or a sedating antidepressant may be the best treatment
option. However, studies documenting effectiveness of this
approach are lacking.
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 Chapter 25 Insomnia 507

Improved Continue

Insomnia
hypnotic indicated
Duration of
action too long Use shorter
acting BZRA
AM grogginess

Consider: cost, prior

treatment failures and side
effects, co-morbid
conditions, drug interactions
Duration of Continue
Use longer Yes
action not
acting BZRA
long enough
Improved? BZRA
+ sedating
Short to intermediate antidepressant
acting BZRA or Ramelteon
Not Higher dose No
SOI Zaleplon, Ramelteon or switch to
effective
alternate BZRA or
SOI, SMI zolpidem,
eszopiclone, temazepam
Sedating
antidepressant

Side effects Switch to

not tolerated alternate BZRA

FIGURE 259 Clinical pathway for hypnotic treatment of insomnia. BZRA = benzodiazepine receptor agonist; SMI = sleep-maintenance insomnia; SOI = sleep-
onset insomnia. Adapted from Schutte-Rodin S, Broch L, Buysee D, et al: Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin
Sleep Med 2008;4:487504.

Pharmacotherapy of Insomnia: Overall Strategy

A general strategy for hypnotic therapy for insomnia7 is illus-
trated in Figure 259. After considering factors listed in
Table 2513, one could start with ramelteon or zaleplon for
sleep-onset insomnia. If sleep-maintenance insomnia is a
problem, use of zolpidem, zolpidem CR, eszopiclone, or
temazepam could be considered. In elderly patients or
patients with impaired hepatic metabolism, a lower hyp-
notic dose is prudent. If the duration of action is not long
enough, one can switch to a longer-acting medication. For
example, a switch from zolpidem to eszopiclone. If the dura-
tion of action is too long (AM sedation), a switch to a shorter-
acting medication or a reduction in dose of the current
medication could be tried. If the medication is not effective,
a switch to an alternate BZRA or a change from ramelteon
to a BZRA could be considered. Some patients will respond
differently to alternate BZRAs. Temazepam may not work
well for sleep-onset insomnia in some patients due to its
longer onset of action. If anxiety is a major component of
insomnia, use of a traditional BZ (e.g., temazepam) or eszop-
iclone with more anxiolytic activity might be more effective.
Recall that zaleplon and zolpidem have little anxiolytic activ-
ity. If the current hypnotic medication is not tolerated due
to side effects, a switch to an alternate BZRA could also be
tried.
If treatment with standard BZRA hypnotics is not suc-
cessful, one could try a sedating antidepressant. Given the
minimal anticholinergic effects associated with trazodone,
most physicians would start with this medication when
using a sedating antidepressant. However, low-dose doxepin
or amitriptyline may be effective in some patients. If sedating
antidepressants are not effective (or tolerated at an effective
dose), the combination of a BZRA and a sedating antidepres-
sant could be tried (e.g., zolpidem and trazodone).
If patients have a significant pain component to their
insomnia, one could try gabapentin for its sedating as well
as analgesic effects. If anxiety is a major component of the
insomnia or the traditional BZRA hypnotics are not effec-
tive, use of lorazepam or clonazepam could be tried. Lastly,
one could try a sedating antipsychotic medication in low
doses (quetiapine). These drugs have major side effects and
are generally to be avoided unless a mental disorder is present
or all other options have failed.
CLINICAL REVIEW QUESTIONS
1. A 40-year-old man was prescribed zolpidem for insomnia
complaints. His problems with sleep onset have improved
but he is still unable to sleep later than 3 to 4 AM. What
medication do you prescribe?
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508 Chapter 25 Insomnia

A. Zaleplon. D. Eszopiclone.
B. Eszopiclone. E. Ramelteon.
C. Flurazepam.
7. A 45-year-old woman complains of not sleeping at all
D. Ramelteon.
for 2 to 3 nights each week. Other nights, it takes over
2. Which of the following behavioral techniques has the an hour to fall asleep and the TST is never over 4 hours.
least evidence of its efficacy? The patient rarely takes naps but feels terrible the next
A. SCT. day when she does not sleep the night before. The patient
describes laying in bed all night thinking about her
B. RT.
work. She kept a sleep log and was studied with actigra-
C. SRT. phy. One night no sleep was reported but the actigraph
D. Sleep hygiene education. estimated about 5 hours of sleep. What is the most likely
E. Multimodality therapy diagnosis?
A. Idiopathic insomnia.
3. A 60-year-old obese man has a history of alcohol depen-
B. Psychophysiologic insomnia.
dence, insomnia, and benign prostatic hypertrophy.
What is the most appropriate medication for treatment C. Paradoxical insomnia.
of his insomnia? D. Insomnia associated with a mood disorder.
A. Doxepin 25 mg. 8. What of the following is NOT true about the GABAA
B. Amitriptyline 25 mg. receptor complex?
C. Zolpidem 10 mg. A. It contains a chloride ionophore.
D. Trazodone 50 mg. B. It is composed of five protein subunits.
E. Diphenhydramine 25 mg. C. Binding of a BZRA opens the chloride pore.
4. A 30-year-old woman reports problems with insomnia D. The complex is usually composed of two alpha, two
since childhood. There have been no periods of remis- beta, and one gamma subunits.
sion. She denies sleeping better in novel environments.
9. Which of the following medications is associated with
During the last few months, her mood and sleep com-
an unpleasant taste?
plaints have worsened. What is the most likely
diagnosis? A. Zolpidem.
A. Psychophysiologic insomnia. B. Eszopiclone.
B. Idiopathic insomnia. C. Ramelteon.
C. Paradoxical insomnia. D. Trazodone.
D. IDMD. 10. Which of the following statements about CBTI is not
true?
5. A 30-year-old man complains of episodes of waking up
at 3 AM and not being able to return to sleep. These epi- A. It consists of cognitive therapy and one or more of
these behavioral treatments (SCT, SRT) with or
sodes occur about every 2 weeks but are not predictable.
without RT.
What do you prescribe?
B. It continues to show benefits after the treatment
A. Zolpidem.
period.
B. Zaleplon.
C. It is more effective if combined with hypnotic
C. Eszopiclone. treatment.
D. Temazepam. D. It is effective for both primary and secondary
6. A 50-year-old woman is taking a hypnotic for insomnia. insomnia.
Recently, she has been sleepwalking and eating during 11. A 5-year-old boy often awakens during the night and
sleep. Some episodes she can remember but other times will not return to sleep without at least 1 2 hour of paren-
she is surprised to find evidence of food consumption tal presence and attention. Which diagnosis best
when she awakens in the morning. Although the behav- describes the problem?
ior could occur with almost any hypnotic, which of the
A. Childhood behavioral insomnialimit-setting type.
following BZRAs has been most often associated with
the behavior. B. Childhood behavioral insomniasleep-association
type.
A. Zaleplon.
B. Temazepam. 12. A 50-year-old man with both sleep-onset and
C. Zolpidem. sleep-maintenance insomnia is started on 12.5 mg of
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 Chapter 25 Insomnia 509

PM Midnight AM Noon PM
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6

Sun Mon

Mon Tues

Tues Wed

Wed Thurs

Thurs Fri

Fri Sat

Sat Sun

Asleep In bed Out of bed

FIGURE 2510

zolpidem CR. He tolerated the medication and falls
asleep quickly but awakens at 4 AM. Which of the follow-
ing is the most appropriate next step?
A. Eszopiclone.
B. Trazodone.
C. Quetiapine.
D. Ramelteon.
E. Zaleplon.
13. Which of the following is NOT true about adjustment
insomnia?
A. Duration must be less than 3 months.
B. It is associated with an identifiable stressor.
C. It is expected to resolve spontaneously in most
cases.
D. Duration must be less than 1 month.
14. A patient complains of sleep-onset and sleep-
maintenance insomnia. A sleep log is shown in Figure
2510. Which of the behavioral techniques would be
most applicable to this patient?
A. RT.
B. SCT.
C. Sleep hygiene education.
D. SRT.
Answers
1. B. A BZRA with a longer duration of action is needed.
Zaleplon and ramelteon are short acting. Flurazepam is
very long acting and often associated with daytime
sedation.
2. D. There is no evidence that sleep hygiene education
alone is effective treatment for insomnia.
3. D. Trazodone. Doxepin (at 25 mg), amitriptyline, and
diphenhydramine all have significant anticholinergic
activity and could cause urinary retention. Use of zolpi-
dem is relatively contraindicated in a patient with
current or prior substance dependence. Trazodone has
minimal anticholinergic activity. Recently, low-dose
doxepin (1, 3, and 6 mg) has been used and this might
be another alternative. In patients with drug depen-
dence, BZRAs should be avoided if possible.
4. B. Idiopathic insomnia is characteristically present
since childhood without periods of remission. Psycho-
physiologic and paradoxical insomnia are not present
since childhood. IDMD would be a reasonable possibil-
ity but the patient had significant insomnia many years
before her mood worsened.
5. B. Zaleplon is the only medication on the list with a
very short half-life. It is most appropriate for rescue
medication for middle of the night awakening. It should
not be used if there are not at least 3 to 4 more hours of
possible sleep. If the patient could predict which nights
were associated with middle of the night awakening, use
of a longer-acting medication at bedtime might also be
appropriate.
6. C. Zolpidem is the BZRA most associated with sleep-
walking, sleep violence, and the sleep-related eating dis-
order. However, all BZRAs could be associated with
these problems.
7. C. Paradoxical insomnia is associated with extreme
reduction in reported sleep times but relatively little
daytime impairment relative to the reported sleep loss.
The subjective amount of sleep loss always far exceeds
objective determination (PSG or actigraph)
8. C. BZRA binding alone is not sufficient to open the
pore. Rather, BZRA binding enhances the ability of
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510 Chapter 25 Insomnia
GABA binding to open the pore. BZRAs are GABAA
receptor modulators (enhancers).
9. B.
10. C. Studies have not shown advantage to combining
hypnotic treatment with CBTI.
11. B.
12. A. Patients may respond differently to different BZRAs.
Because zolpidem CR was tolerated, using another
intermediate-acting BZRA is a reasonable next step.
Eszopiclone (has a longer duration of action than zolpi-
dem CR in some patients) or temazepam are options.
Trazodone might work but there is less evidence for
efficacy than other BZRAs. The addition of trazodone to
zolpidem CR is another option. Quetiapine is an anti-
psychotic with many side effects. Ramelteon and
zaleplon would not be appropriate for sleep-maintenance
insomnia.
13. A. The duration must be less than 3 months. Adjust-
ment insomnia is associated with an identifiable stressor
and would meet the definition of insomnia only if
present for at least 1 month.
14. D. Although all the above behavioral treatments could
potentially be helpful, SRT is the one most suggested by
the sleep log (see Fig. 2510). The patient stays in bed
almost 12 hours most days. By shortening the time in
bed, hopefully the sleep efficiency will increase.
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dose-response study of ramelteon in patients with chronic
primary insomnia. Sleep Med 2006;7:1724.
71. Mayer G, Wang-Weigand S, Roth-Schechter B, et al: Efficacy
and safety of 6 month nightly ramelteon administration in
adults with chronic primary insomnia. Sleep 2009;32:351360.
72. Zammit G, Erman M, Wang-Weigand S, et al: Evaluation of the
efficacy and safety of ramelteon in subjects with chronic insom-
nia. J Clin Sleep Med 2007;3:495504.
73. Mendelson W: A review of the evidence for the efficacy and
safety of trazodone in insomnia. J Clin Psychiatry 2005;66:
469476.
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512 Chapter 25 Insomnia
74. Walsh J, Erman M, Erwin CW, et al: Subjective hypnotic effi-
cacy of trazodone and zolpidem in DSMIII-R primary insom-
nia. Hum Psychopharmacol 1998;13:191198.
75. Kaynak H, Kaynak D, Gzkirmizi E, et al: The effects of tra-
zodone on sleep in patients treated with stimulant antidepres-
sants. Sleep Med 2004;5:1520.
76. Nierenberg AA, Adler LA, Peselow E, et al: Trazodone for
antidepressant associated insomnia. Am J Psychiatry 1993;151:
10691072.
77. Winkour A, DeMartins NA, McNally DP, et al: Comparative
effects of mirtazapine and fluoxetine on sleep physiology mea-
sures in patients with major depression and insomnia. J Clin
Psychiatry 2003;64:12241229.
78. Roth T, Rogowski R, Hull S, et al: Efficacy and safety of doxepin
1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep
2007;30:15551561.
79. Brzezinski A, Vangel MG, Wurtman RJ, et al: Effects of exog-
enous melatonin on sleep. A meta analysis. Sleep Med Rev
2005;9:4150.
80. Morin CM, Koetter U, Bastien C, et al: Valerian-hops combina-
tion and diphenhydramine for treating insomnia: a randomized
placebo controlled clinical trial. Sleep 2005;28:14651471.
81. Fava M, McCall V, Krystal A, et al: Eszopiclone co-administered
with fluoxetine in patients with insomnia coexisting with major
depressive disorder. Biol Psychiatry 2006;59:10521060.
82. Fava M, Asnis G, Shrivastava R, et al: Zolpidem extended
release 12.5 mg co-administered with escitalopram, improves
insomnia in patients with comorbid insomnia and major
depressive disorder improved insomnia symptoms and next
day function in patients with co-morbid disorder. Presented at
the American Psychiatric Association 161st Annual Meeting,
Washington, DC, 2008.
83. Fava M, Asnis GM, Shrivastava R, et al: Zolpidem extended
release improves sleep and next-day symptoms in comorbid
insomnia and generalized anxiety disorder. J Clin Psychophar-
macol 2009;29:222230.
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 Appendix 25-1

Dysfunctional Beliefs and Attitudes

about Sleep Worksheet
The DBAS is administered by asking patients to endorse each 8 9 10) with 0 = strongly disagree and 10 = strongly
statement using a Likert scale (0 1 2 3 4 5 6 7 agree.

From Morin CM; Vallires A; Ivers H: Dysfunctional Beliefs and Attitudes about Sleep (DBAS): validation of a brief version (DBAS-16). Sleep
2007;30:15471554.
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514 Chapter 25 Insomnia

DYSFUNCTIONAL BELIEFS AND ATTITUDES ABOUT SLEEP (DBAS)

Name: Date:

Several statements reflecting peoples beliefs and attitudes about sleep are listed below. Please
indicate to what extent you personally agree or disagree with each statement. There is no right
or wrong answer. For each statement, circle the number that corresponds to your own personal
belief. Please respond to all items even though some may not apply directly to your own
situation.
Strongly Strongly
disagree agree
0 1 2 3 4 5 6 7 8 9 10

1. I need 8 hours of sleep to feel refreshed and function well during the day.

0 1 2 3 4 5 6 7 8 9 10
2. When I dont get proper amount of sleep on a given night, I need to catch up on the next day
by napping or on the next night by sleeping longer.

0 1 2 3 4 5 6 7 8 9 10
3. I am concerned that chronic insomnia may have serious consequences on my physical health.

0 1 2 3 4 5 6 7 8 9 10
4. I am worried that I may lose control over my abilities to sleep.

0 1 2 3 4 5 6 7 8 9 10
5. After a poor nights sleep, I know that it will interfere with my daily activities on the next day.

0 1 2 3 4 5 6 7 8 9 10
6. In order to be alert and function well during the day, I believe I would be better off taking a
sleeping pill rather than having a poor nights sleep.

0 1 2 3 4 5 6 7 8 9 10
7. When I feel irritable, depressed, or anxious during the day, it is mostly because I did not sleep
well the night before.

0 1 2 3 4 5 6 7 8 9 10
8. When I sleep poorly on one night, I know it will disturb my sleep schedule for the whole week.

0 1 2 3 4 5 6 7 8 9 10
9. Without an adequate nights sleep, I can hardly function the next day.

0 1 2 3 4 5 6 7 8 9 10
10. I cant ever predict whether Ill have a good or poor nights sleep.

0 1 2 3 4 5 6 7 8 9 10
11. I have little ability to manage the negative consequences of disturbed sleep.

0 1 2 3 4 5 6 7 8 9 10
12. When I feel tired, have no energy, or just seem not to function well during the day, it is
generally because I did not sleep well the night before.

0 1 2 3 4 5 6 7 8 9 10
13. I believe insomnia is essentially the result of a chemical imbalance.

0 1 2 3 4 5 6 7 8 9 10
14. I feel insomnia is ruining my ability to enjoy life and prevents me from doing what I want.

0 1 2 3 4 5 6 7 8 9 10
15. Medication is probably the only solution to sleeplessness.

0 1 2 3 4 5 6 7 8 9 10
16. I avoid or cancel obligations (social, family) after a poor nights sleep.

0 1 2 3 4 5 6 7 8 9 10

DaneshGroup.com

Circadian Rhythm
Sleep Disorders
Chapter Points
In humans, the normal circadian period (tau) is
approximately 24.2 hours (mean value). Because the
period is slightly longer than 24 hours, this requires a
slight phase advance daily to maintain entrainment
with the light-dark cycle.
The major circadian pacemaker in humans is the SCN.
The SCN is entrained to the light-dark cycle via light
stimulation of retinal melanopsin-containing pRGCs.
The ganglion cells communicate via the RHT to the
SCN. Blue light has the most potent effect.
The alerting signal from the SCN increases during the
day to counter the increasing homeostatic sleep drive
(accumulated wake since the last sleep). The alerting
signal falls during sleep and the homeostatic sleep
drive also falls.
Melatonin is secreted in darkness by the pineal gland.
Light inhibits melatonin secretion by decreasing the
activating influences of neurons in the PVH nucleus.
The neural pathway from the PVH neurons to the pineal
gland is circuitous passing through the spinal cord and
superior cervical ganglion (see Fig. 262). Melatonin
binds to receptors on the SCN and decreases the
alerting signal during darkness (promoting sleep).
The CBTmin occurs about 2 hours before the habitual
wake time.
DLMO is the time that serum melatonin starts to
increase above daytime levels under dim light
conditions and occurs about 2 to 3 hours before
bedtime or 7 hours before CBTmin.
CBTmin and DLMO can be used as markers of circadian
phase. When the circadian rhythm of the body
(CBTmin or DLMO) moves to a later clock time, this is
said to represent a phase delay in circadian rhythms
and to an early time phase advance.
Light after the CBTmin induces a phase advance and
light before the CBTmin induces a phase delay.
Melatonin administered before the CBTmin induces a
phase advance. Melatonin given after the CBTmin
induces a phase delay.
Chapter 26
Bright light pushes and melatonin pulls on the
circadian phase (CBTmin)
The DSPD is characterized by a delay in sleep
period relative to clock time, characterized by late
sleep onset and late natural awakening. The DSPD
is the most common CRSD seen in sleep clinics
and presents as sleep-onset insomnia. If undisturbed
by social obligations, patients with DSPD have
good sleep maintenance and awaken feeling
refreshed.
Treatments for the DSPD include bright light at or
slightly before the natural (unrestricted) wake time
(timed to follow CBTmin) or melatonin 5 to 7 hours
before habitual sleep-onset time. Both melatonin and
light can be used. The patient attempts to go to bed
about 12 hour earlier each night and the timing of
application of melatonin and light is changed to
maintain the initial relationship.
The ASPD is characterized by an advance in the sleep
period relative to clock time characterized by early
sleep onset and early awakening. It occurs most
commonly in elderly individuals.
The CRSD-FRT is characterized by a progressive phase
delay of 1 to 2 hours per day. It is most common in
blind individuals but can occur in sighted individuals
and has been described after head trauma.
The treatment for nonsighted patients with the
CRSD-FRT is melatonin given about 1 hour before the
desired bedtime. In some studies, a lower dose was
more effective than a large dose.
The ISWR is characterized by at least three different
periods of sleep during 24 hours (usually normal total
sleep time). This CRSD is most common in elderly
patients in nursing homes or institutionalized severely
mentally impaired young patients. Treatments include
bright light during the day, structured daily activities,
and decreased noise and light at night. Melatonin at
night is recommended for younger patients with
mental retardation but not for elderly nursing home
patients.
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516 Chapter 26 Circadian Rhythm Sleep Disorders
Approximately 10% of patients working a night shift
have complaints of difficulty staying awake at night or
sleeping during the day that are severe enough to be
considered an SWD.
Treatment for night shift workers includes scheduled
naps before the shift, bright light during the start of
the shift, stimulants (caffeine or modafinil) at the start
of the shift, dark glasses on the drive home (if after
sunrise), and melatonin or hypnotics before the
daytime sleep period. The major sleep period should
occur soon after arriving home from work. The sleep
environment should be as quiet and dark as possible.
Jet lag is characterized by a misalignment between
endogenous circadian rhythms and local time caused
by rapid travel across at least two time zones.
Eastward travel requires adaptation by a phase
advance and adaptation is more difficult than
westward travel. Westward travel requires adaptation
by a phase delay and adaptation is easier because of
the intrinsic tendency for phase delay. Trying to avoid
light at times inducing the wrong phase shift and
receiving light exposure at correct times inducing the
desired phase shift at the new destination are
recommended. Melatonin before the desired sleep
period or hypnotics may be helpful. Most individuals
require about 1 day of adaptation for each time zone
crossed.
The word circadian means about a day and describes pro-
cesses that vary over time with approximately a 24-hour
period. In humans, many physiologic processes vary periodi-
cally on a nearly 24-hour schedule.1,2 The major circadian
pacemaker in mammals is the suprachiasmatic nucleus
(SCN) in the anterior hypothalamus. The nucleus exists as
paired structures on each side of the third ventricle above
the optic chiasm.24 The SCN contains cells that oscillate
independently with a period slightly longer than 24 hours.
The SCN controls the rhythms of core body temperature and
sleep-wake propensity as well as the secretion of certain hor-
mones (melatonin and cortisol). The period of the rhythm is
called tau and the mean value in humans is about 24.2
hours.3 Some individuals have a slightly shorter tau and
some longer. For humans to maintain synchrony with the
light-dark cycle, external stimuli must induce a slight daily
advance (shift in circadian rhythms to an earlier clock time)
to counteract the intrinsic tendency for phase delay due to a
period slightly longer than 24 hours. These external stimuli
called zeitgebers (time givers) are said to entrain the SCN
to the light-dark cycle.
The most potent zeitgeber is nonvisual light informa-
tion. Other zeitgebers include exercise, food, and social
activities. The light stimulus reaches the SCN via the retino-
hypothalamic tract (RHT) (Fig. 261). The RHT is a mono-
synaptic pathway connecting the melanopsin-containing
photosensitive retinal ganglion cells (pRGCs) to the SCN.
SCN [Melatonin]
Light RHT Pineal
Superior cervical
ganglia
FIGURE 261 Light information travels via the retinohypothalamic tract (RHT) to the
suprachiasmatic nucleus (SCN). The SCN then signals the pineal via a complex neural
pathway passing through the superior cervical ganglion and inhibits melatonin
production. In the absence of light (during dark), the inhibition is removed and the
pineal secretes melatonin. The melatonin then acts on the SCN to decrease the alerting
signal. From Reid KJ, Zee PC: Circadian rhythm disorders. Semin Neurol 2009;29:
393405.
Nonvisual photoreception also mediates the pupillary light
response. Some blind patients continue to be entrained by
light due to residual function of the retinal ganglion cells.
Whereas the ganglion cells are the major circadian photosen-
sors, the rods and cones also contribute some nonvisual
information via communication with the pRGCs.4,5 The
shorter wavelengths of light (blue) have the greatest effect
on circadian rhythms. The primary neurotransmitter of the
retinal ganglion cell neurons in the RHT is glutamate.
However, the neurons also release pituitary adenyl cyclase
activating peptide (PACP) as a co-transmitter that causes
similar effects on the SCN neurons. The effects of glutamate
are mediated by binding to N-methyl-D-aspartate (NMDA)-
type glutamate receptors and the subsequent elevations of
intracellular calcium and nitric oxide in the neurons of the
SCN. PACP-containing fibers from the retinal ganglion cells
also project to the intergeniculate leaflet (IGL), which in
turn, project to the SCN. Neurons in the IGL use gamma-
aminobutyric acid (GABA) and neuropeptide Y as co-
transmitters. Neurons in the IGL may mediate some of the
phase-shifting influences of exercise on the SCN. As is dis-
cussed later, the intensity, the duration, and the timing of
light exposure determine the effect of light on the circadian
system.
MELATONIN
The pineal gland secretes a hormone called melatonin during
the dark cycle.411 In the absence of light, certain dorsal par-
vocellular neurons in the autonomic subdivision of the para-
ventricular hypothalamic nucleus (PVH) provide tonic
stimulation to the pineal gland via a circuitous pathway47
DaneshGroup.com

Melatonin
SCN 
PVH
MT2 MT1 
Retinal
ganglion
cell
Light
NE
Glutamate
Eye Pre-ganglionic
neuron
Interomedial Ach
lateral column Post-ganglionic cell
of upper thoracic
Superior
spinal cord
cervical
ganglion
(Fig. 262). These PVH glutaminergic neurons project to
sympathetic preganglionic neurons in the intermediolateral
cell column (IML) of the upper thoracic spinal cord. The
preganglionic sympathetic neurons provide a cholinergic
projection to postganglionic neurons located in the superior
cervical ganglion. The postganglionic neurons are noradren-
ergic and project to the pineal gland. The release of norepi-
nephrine stimulates the pineal gland via alpha and beta
receptors (mainly beta 1). Noradrenergic stimulation on the
pineal gland results in increased cyclic adenosine mono-
phosphate (AMP) in the pinealocytes and this induces
expression of serotonin N-acetyltransferase (also known as
arylalkylamine N-acetyltransferase [AA-NAT]). This enzyme
catalyzes the rate-limiting step in the synthesis of melatonin.
Therefore, the amount of this enzyme controls the produc-
tion of melatonin.
In the presence of light, some neurons of the SCN directly
inhibit those neurons in the PVH that are responsible for
stimulating the pineal gland to secrete melatonin. Thus, light
inhibits melatonin secretion and the absence of inhibition
(absence of light) allows secretion of melatonin. Melatonin
is sometimes called the dark hormone. The melatonin
secreted by the pineal gland provides inhibitory feedback
information to SCN neurons. Therefore, the SCN and pineal
gland are mutually inhibitory. Important facts about human
circadian rhythms are summarized in Box 261.
Melatonin is not essential for circadian rhythms in
humans because removal of the pineal gland has minimal
effects. In other species such as birds, the pineal gland is
essential. The SCN has a high density of two types of mela-
tonin receptors (MT1 and MT2). The MT1 receptor is a G
proteincoupled receptor that activates protein kinase C.
When melatonin binds the MT1 receptor on SCN neurons,
this decreases SCN-alerting signal. The MT2 receptor is a G
proteincoupled receptor that inhibits the guanine cyclase
pathway and results in a shift in circadian phase. A third type
of melatonin receptor (MT3) does not affect the pineal gland.
Exogenous melatonin by oral administration can also affect
Chapter 26 Circadian Rhythm Sleep Disorders 517
FIGURE 262 The suprachiasmatic nucleus (SCN) inhibits melatonin
secretion by the pineal via a complicated neural pathway. In the absence
Pineal of light, dorsal parvocellular neurons in the autonomic subdivision of the
gland
paraventricular hypothalamus (PVH) send a tonic signal (glutamate)
Alpha, beta stimulating preganglionic sympathetic neurons in the thoracic spinal cord
sympathetic that then project to the superior cervical ganglion and stimulate
receptors postganglionic neurons. These noradrenergic neurons innervate the pineal
gland. Norepinephrine (NE) acting at alpha and beta receptors on the
pineal gland results in production and secretion of melatonin. A subset of
SCN neurons project directly to the PVH neurons at the origin of the
pathway providing stimulation to the pineal gland. When light is present,
the SCN inhibits the PVH neurons. In the absence of inhibition (by light),
melatonin is produced and secreted by the pineal gland. Ach =
acetylcholine; MT = melatonin.
BOX 261
Circadian PhysiologyImportant Facts
Circadian (about a day) denotes processes with
approximately a 24-hr period.
The human period of circadian rhythms (tau) is about
24.2 hr.
SCN is the major circadian pacemaker in humans.
SCN function helps maintain alertness by producing an
alerting signal during the day and maintaining sleep by a
reduced signal at night.
Usual human alertness:
Midday decrease in alertness 24 PM.
Alertness peaks in the early evening hours.
Lowest levels of alertness occur from 46 AM.
Zeitgebers (time givers) entrain the SCN to the physical
environment.
Light (sunlight) is the major zeitgeber.
Melanopsin-containing retinal ganglion cells are the
major circadian photoreceptors and communicate the
presence of light to the SCN via the RHT.
RHT = retinohypothalamic tract; SCN = suprachiasmatic nucleus.
the SCN. The half-life of exogenous melatonin is short (30
45 min) unless sustained-release melatonin preparations are
used. As might be expected, the effects of exogenous mela-
tonin are largest when no endogenous melatonin is being
secreted.8 Exogenous melatonin can decrease the SCN-
alerting signal (hypnotic effects) and cause a phase shift of
circadian rhythms (discussed in a later section). Melatonin
acting on blood vessels in the skin causes vasodilatation and
increased blood flow results in heat loss and lowering of the
body temperature.
THE SCN AND SLEEP-WAKE CYCLE
The SCN helps maintain alertness by producing an alerting
signal during the day and helps maintains sleep by producing
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518 Chapter 26 Circadian Rhythm Sleep Disorders

TABLE 261
Sleep load Wake Sleep-Wake Regulation
Nighttime First part Homeostatic drive is high
sleep of night (from awake all day).
Circadian alerting signal is
low.
Second Homeostatic drive is lower.
part of Circadian alerting signal is
night low.
Alerting Sleep
signal Daytime First part Homeostatic drive is low
wakefulness of day (due to prior sleep).
Circadian drive is increasing.
9AM 3PM 9PM 3AM 9AM Second Homeostatic drive is high
part of and increasing (prior wake).
FIGURE 263 Opponent model of sleep. The sleep load (down arrows) increases
day Circadian alerting signal is
proportional to the amount of prior wake and decreases with sleep onset. It is opposed
high (compensation).
by the alerting signal from the SCN (up arrows). The alerting signal increases to a
maximum just before sleep onset to help maintain wakefulness (the forbidden sleep
period) but then decreases during the sleep period so that sleep can occur. The solid line
is the wake-sleep propensity. Note a small dip in the afternoon. Adapted from Edgar
DM, Dement WC, Fuller CA: Effect of SCN lesions on sleep in the squirrel monkey: evidence BOX 262
for opponent processes in sleep-wake regulation. J Neuorsci 1993;13:10651079. Markers of Circadian Phase
CBTmin occurs 23 hr before awakening from
unconstrained sleep (45 AM)
DLMO occurs ~23 hr before typical sleep onset
a reduced signal at night. The other major influence on sleep
CBTmin = DLMO + 7 (i.e., CBTmin occurs about 7 hr later
propensity is the amount of accumulated wakefulness (time than DLMO)
since the last sleep). This homeostatic process (sleep load)
CBTmin = core body temperature minimum; DLMO = dim light melatonin
builds during wakefulness and then falls during sleep. As the onset.
pressure for sleep builds, the circadian signal increases to
help maintain alertness despite a growing sleep debt but then
decreases so that sleep can occur (Fig. 263). The two-
process model considers the interaction of process S (homeo-
MARKERS OF CIRCADIAN PHASE
static sleep drive) and process C (circadian rhythms, driven
in large part by the SCN). The opponent model of sleep2,9 The minimum of the core body temperature (CBTmin) and
(SCN-alerting signal vs. sleep load) is illustrated in Figure the dim light melatonin onset (DLMO) are two useful
263. Alertness peaks during the early evening hours. There markers of the position of an individuals circadian rhythms
is a midday decrease in alertness around 2 to 4 PM and the with respect to the external environment (i.e., time of day)
lowest alertness is 4 to 6 AM. The interaction of the opponent (Box 262). The CBTmin occurs about 2 hours before spon-
processes (homeostatic sleep load and circadian alerting taneous awakening from nocturnal sleep (45 AM in most
signal) allows humans to be alert during the day and to sleep individuals) (Fig. 264).1012 The reduction in core body tem-
at night (Table 261). The secretion of melatonin at night perature during the sleep period corresponds to the eleva-
exerts an inhibitory influence on the SCN that helps main- tion in plasma melatonin. The wakefulness in sleep episode
tain sleep by reducing the alerting signal. is an estimate of the wake propensity and is maximum in the
The pathways by which the alerting signal of the SCN evening before the sleep period and falls during sleep.
regulates sleep-wake are complex.2,5 One of the major path- The DLMO occurs about 2 to 3 hours before typical
ways is as follows. Neurons in the SCN project to neurons in bedtime.1015 One can estimate the timing of the CBTmin as
the ventral subparaventricular zone (vSPZ). This area is DLMO + 7 hours (see Box 262). The DLMO is determined
immediately dorsal to the SCN. Neurons in the vSPZ then by interval measurement of salivary or plasma melatonin
project to the dorsal medial hypothalamus (DMH). Gluta- performed in dim light (5 lux; because light inhibits melato-
minergic neurons in the DMH project to the lateral hypo- nin secretion) in the evening. A rise in melatonin levels
thalamus neurons producing hypocretin (stabilizing detects the DLMO time (Fig. 265). The melatonin mid-
wake-to-sleep transitions). In addition, DMH neurons using point can also be used as a circadian marker and occurs
GABA as an inhibitory neurotransmitter project to the ven- about 2 hours before CBTmin. When the circadian rhythm
trolateral preoptic area (VLPO), a sleep-promoting area. of the body (CBTmin or DLMO) moves to a later clock time,
These pathways mediate some of the effect of the SCN- this is said to represent a phase delay in circadian rhythms
alerting signal by inhibiting sleep-promoting areas and stim- and to an early time phase advance. The relationship between
ulating areas stabilizing transitions from wake to sleep. the timing of sleep and the circadian phase (as estimated by
DaneshGroup.com
 Chapter 26 Circadian Rhythm Sleep Disorders 519

Clock time FIGURE 264 Schematic representation of the sleep period

6 9 12 15 18 21 24 3 6 9 12 15 18 21 24 3 6 of a young adult. The minimum of core body temperature
(depicted as the vertical dotted line) occurs about 2 hours before
Sleep the end of the sleep period. The core body temperature
minimum (CBTmin) also occurs about 1 to 2 hours after the
40 midpoint of melatonin secretion. The amount of wakefulness in
in sleep episode

sleep (a measure of wake propensity) increases (sleep forbidden

Wakefulness

30
(minutes)

zone) just before the sleep period but falls with the onset of
20 melatonin secretion. From Duffy JF, Dijk DJ, Klerman EB, Czeisler
10 CA: Later endogenous circadian temperature nadir relative to
an earlier wake time in older people. Am J Physiol 1998;
0
2 275:R1478R1487.
(mean Z-score)
(difference from mean) melatonin

1
Plasma

1
Body temperature

0.4
(degrees F)

0.0

0.4
360 240 120 0 120 240 360
Circadian phase of core body temperature
(degrees)

21 70
Normal 60
50
18 40
30
20
Melatonin (pg/ml)

15
DSPD 10
0 0
MEL (pg/ml)

12 5
10
9 10
15

Day
20
6
25
10
3 30
6A 6P 6A 6P
t

ht
gh

gh

g
n

n
ni

ni

ni

0
oo

oo
id

id

id
N

N
M

M
19:00

20:00

21:00

22:00

23:00

24:00

01:00

02:00

03:00

04:00

FIGURE 265 Salivary melatonin (MEL) for a normal individual and one with delayed
sleep phase disorder (DSPD). The dim light melatonin onset (DLMO) is taken as the time
at which melatonin reaches 3 pg/mL. This is around 23:00 in the normal individual but
is delayed to around 02:30 in the morning in an individual with DSPD. From Wyatt JK,
Stepanski EJ, Kirkby J: Circadian phase in delayed sleep phase syndrome: predictors and
temporal stability across multiple assessments. Sleep 2006;29:10751080.
a circadian marker) can be quantified by the time interval
(phase angle) between the two rhythms. In Figure 266, the
progressive delay in the DLMO is evidence of a progressive
delay in circadian rhythm in a patient with the circadian
rhythm sleep disorderfree-running type (CRSD-FRT),
also called the free-running disorder (FRD).14
FIGURE 266 Melatonin secretion is shown for a patient whose DLMO (large circles)
occurs progressively later (free-running type of circadian rhythm sleep disorder).
Reproduced from Sack RK, Brandes RW, Kendall AR, Lewy AJ: Entrainment of free-running
circadian rhythms by melatonin in blind people. N Engl J Med 2000;343:10701077.
Use of the core body temperature as a marker of circadian
rhythms is complicated by the fact that eating, activity, and
sleep can affect the timing of CBTmin. In research settings,
a constant routine protocol is utilized in which the subject is
kept awake at bedrest and fed equally distributed small meals
for at least 24 hours. An alternative to the constant routine
protocol is to use mathematical adjustments to the tempera-
ture rhythm. The DLMO can be affected (masked) by posture
and drugs such as beta blockers and caffeine. One can
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520 Chapter 26 Circadian Rhythm Sleep Disorders

FIGURE 267 Phase shifting of the core body CBTmin

temperature minimum (CBTmin) with light. Light Pre-light
Light Post-light
after the CBTmin phase advances and light before

Body temperature (C)

CBTmin phase delays. From Berry RB: Sleep Medicine 37.6
Pearls, 2nd ed. Philadelphia: Hanley & Belfus, 2003,
p. 344.
37.0
Phase advance
36.4

12 16 20 24 4 8 12 12 16 20 24 4 8 12
Time of day Time of day

Light
Body temperature (C) Phase delay
37.6

37.0

36.4

12 16 20 24 4 8 12 12 16 20 24 4 8 12
Time of day Time of day

monitor plasma melatonin (threshold > 10 pg/mL), salivary BOX 263

melatonin (>3 pg/mL), or urinary melatonin metabolite Phase Shifting with Light
(6-sulfatoxymelatonin [aMT6s]) (see Fig. 266).
COMMON LIGHT EXPOSURES
SHIFTING THE CIRCADIAN RHYTHMS Bright blue midday sky >100,000 lux
Sunrise or sunset ~10,000
Phase Shifting by Light Commercial light boxes up to 10,000
Exposure to light before the CBTmin causes a phase delay Normal room light ~200
and light exposure after the CBTmin causes a phase advance Moonlight 0.1 lux
(Fig. 267) in circadian rhythm.1518 Thus, normal light PHASE SHIFTING WITH LIGHT
exposure during the early morning induces a daily phase
Short wavelength light (blue ~460 nm)greatest effect
advance in the circadian rhythms to compensate for the
Amount of phase shift depends on timing, intensity, and
intrinsic tendency to phase delay because tau is slightly
duration of light exposure
longer than 24 hours. The amount of circadian rhythm shift-
Short pulses of light (intermittent) can also shift circadian
ing (also called phase change) depends on the timing of light
rhythms
as well as the intensity and duration of light (Box 263). In
Phase advancelight after CBTmin (~34 hr after CBTmin
addition, the effect depends on the previous exposure to greatest effect)
light.1518 For example, a low intensity of light may cause Phase delaylight before CBTmin (~34 hr before
significant shifting of the circadian rhythms in a patient CBTmin greatest effect)
staying in a dark room for several days. Light intensity is Light in the middle of the dayrelatively little effect
measured in lux. Indoor light is typically around 250 lux and CBTmin = core body temperature minimum.
outdoor bright light has an intensity over 100,000 lux. For
humans exposed to outside light daily (>10,000 lux) for a
portion of each day, a relatively high light intensity is needed
to shift circadian rhythms. Outside daylight is much more patients chronically exposed to much brighter light, a higher
effective at shifting the circadian phase than indoor light. intensity of light would be needed for maximal effect. Natural
When outdoor light exposure is not practical or possible, light is composed of a spectrum from 380 nm (violet) to 760
light boxes are available (2500 lux) for therapeutic phase (red). As noted previously, blue light (460 nm) has greater
shifting by light. One study of subjects kept in a dimly lighted phase shifting properties than the rest of the visible light
environment found that increasing light intensity above spectrum.20 This may be due to the properties of the mela-
550 lux added relatively little to the phase shifting ability of nopsin pigment that has maximum absorbance in this range.
light or the ability to suppress melatonin.19,20 A sigmoid- Recently, light boxes have become available with enriched
shaped relationship was noted (Fig. 268). However, for blue light to minimize the intensity or duration needed for
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 Chapter 26 Circadian Rhythm Sleep Disorders 521

4 100

Melatonin phase shift (hours)

Melatonin suppression (%)

3
80
2

60
1

0 40

1
20
2

3 0
0.1 1 10 100 1000 10000 0.1 1 10 100 1000 10000
A Illuminance (lux) B Illuminance (lux)

FIGURE 268 The amount of phase shifting of melatonin and melatonin suppression against illuminance. The relationship was determined by
a subject kept in a controlled environment with dim light except for the light stimulus being tested. From Zeitzer JM, Dijk DJ, Kronauer RE, et al:
Sensitivity of human circadian pacemaker to nocturnal light: melatonin resetting and suppression. J Physiol 2000;526:695702.

1000 2
CBTmin
Bright light (BL) 1
Phase shift (hours)
Light intensity (lux)

1
0 75 150 225 300 375 0
15 min
1000 1
Intermittent (IBL)
1 2
bright light
0 75 150 225 300 375 3
Control (VDL) 4
1 (very dim light)
0 75 150 225 300 375 0 23 100
Time (minutes) Relative duration of bright
light exposure (%)

FIGURE 269 Intermittent exposure to bright light induces almost as much shift in the core body temperature minimum (CBTmin) as continuous bright
light, although the duration of light exposure was about 23% of the time of continuous exposure. 0% light exposure = baseline; 23% light exposure =
intermittent light exposure; 100% = continuous light exposure. Adapted from Gronifer C, Wright KP, Kronauer RE, et al: Efficacy of a single sequence of
intermittent bright light pulses for delaying circadian phase in humans. Am J Physiol Endocrinol Metab 2004:287:E174E181.

a therapeutic response to light therapy. However, a recent amount of phase shift versus the timing of the light stimulus
study showed no benefit of light enriched with blue light (constant stimulus intensity). By convention, the positive
compared with white light.21 It is possible that new light vertical axis represents phase advances and the negative axis
boxes with light-emitting diode (LED) emission of mono- phase delays. For light, the magnitude of phase shifting
chromatic blue light could be more effective. Intermittent as depends on the proximity to the CBTmin (Fig. 2610). In
well as continuous light is also effective at resetting the cir- most studies, the maximum phase shift occurs approximately
cadian pacemaker22,23 (Fig. 269). This fact has clinical impli- 3 to 4 hours before (phase delay) or after (phase advance) the
cations for delivery light treatment when a patient cannot sit CBTmin (Fig. 2611). Light in the middle of the day has
in front of a light box for long periods of time. minimal phase shifting effects.
Of note, the published PRCs for light vary somewhat
depending on the methodology used to determine the PRC.
Phase-Response Curve for Light
For example, the PRC can be obtained by studying entrained
The relationship between the timing of light exposure and the subjects on a constant routine protocol or non-entrained
amount of phase shift is best presented using a phase response subjects with a free-running routine. Typically, shifts in the
curve (PRC). The curves are constructed by plotting the DLMO are determined for different timing of light pulses.
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 522 Chapter 26 Circadian Rhythm Sleep Disorders

PHASE RESPONSE CURVE TO LIGHT TABLE 262

Advance
Phase Shifting with Melatonin and
Light A Hypnotic Effects
3 Light A - large phase advance PRC approximately opposite to light PRC (12 hr out of
Amount of phase shift (hr)

2 Light B Light B - small phase advance phase).

1 Light C - large phase delay Reversal point (phase advance to phase delay) may be
slightly before minimum of core body temperature but is
0 always considerably after the DLMO.
1 Dose-response curves may vary with dose (0.3 mg vs.
3 mg)
2 Note at larger doses, hypnotic effects are noted.
3 Exogenous melatonin half-life is about 30 to 45 minutes.
Light C Corresponds to timing of Given closer to bedtime, melatonin may reduce SCN
Delay body temperature minimum alerting signal (dampen wake maintenance zone)
FIGURE 2610 Schematic of the phase response curve (PRC) for light. The direction Maximal phase advance for different melatonin doses*
of the phase change depends on whether light is applied before or after CBTmin. The Dose 0.30.5 mg 3 mg
maximum phase advance (Light A) occurs about 3 to 4 hours after CBTmin. If light is
OPTIMAL TIMING
applied 7 to 8 hours after CBTmin (Light B), the phase advance is much smaller. The
maximum phase delay occurs 3 to 4 hours before the CBTmin. At midday to early Before DLMO 23 hr 5 hr
evening, there is little effect of light on the circadian phase. (See also Fig. 2611.)
Before habitual sleep onset 4.55 hr 7.5 hr
Before CBTmin 9 hr 12 hr
Maximal phase delayabout 10 hours after DLMO
*From Eastman CI, Burgess HJ: How to travel the world without jet lag. Sleep
2 Med Clin 2009;4:241255.
CBTmin = core body temperature minimum; DLMO = dim light melatonin
1 onset; PRC = phase response curve; SCN = suprachiasmatic nucleus.
Phase shift (h)

1

2 of melatonin secretion (melatonin midpoint) rather than

DLMO were measured following a single pulse of light.
3 Again, note that the biggest phase shifts occur when light is
4 administered near the CBTmin.
6 9 12 15 18 21 0 3 6 9 12 15 18
Circadian phase Phase Shifting by Exogenous Melatonin
(melatonin midpoint  22 h)
Relatively small doses of exogenous melatonin (0.30.5 mg)
FIGURE 2611 The PRC to bright light using melatonin midpoints as the circadian
can shift the circadian phase (Table 262) if taken at the
phase marker. The determination was made using a constant routine protocol (enforced
correct times. As might be expected, the phase shifting
wakefulness in a semirecumbent position). Phase advances are positive values and
phase delays are negative values. They are plotted against the time of the melatonin effects of exogenous melatonin are minimal during the dark
midpoint (DLMOonset to DLMOoffset). The melatonin midpoint was defined to be 22 period when the endogenous plasma level of melatonin is
hours. The CBTmin is assumed to be 2 hours later (0 hr). The horizontal dashed line high.2426 Melatonin in higher doses (35 mg) has a direct
represents the assumed drift in circadian phase between prestimulus (prelight hypnotic effect8 as well as a chronobiotic effect. However, the
administration) and poststimulus phase assessments (~3 days). From Khalsa SBS, hypnotic effects of melatonin are limited by the drugs short
Jewett ME, Cajocen C, Czeisler CA: A phase response curve to single bright light pulses in half-life and the fact that if taken at night, the endogenous
human subjects. J Physiol 2003;549:945952. plasma melatonin is already high.

Melatonin PRC Curve

The phase shifts in circadian rhythms can also be determined
by shifts in the CBTmin. However, as noted previously, exer-
cise, food, and other activities can affect CBTmin. Shifts in
the DLMO, especially if determined using a constant routine
dim light protocol, are felt to more accurately assess the
circadian phase than CBTmin.
Figure 2611 illustrates a PRC for light. This was deter-
mined using a constant routine, and shifts in the midpoint
The PRC curve for melatonin is roughly 12 hours opposite
(out of phase) to the light PRC2426 (Fig. 2612). In displays
of the melatonin PRC, the timing of melatonin is often
expressed relative to DLMO but can also be expressed rela-
tive to the estimated CBTmin. Melatonin when given in the
early evening before the DLMO results in a phase advance.
Melatonin given at the end of the subjective nightearly sub-
jective day causes a phase delay (see Fig. 2612). As expected,
the melatonin PRC has flat region (no phase shifting)
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 Chapter 26 Circadian Rhythm Sleep Disorders 523

Melatonin CBTmin Light FIGURE 2612 Phase response curves (PRCs) for light and
3 3 melatonin (3 mg). The position of DLMO and the core body
Light PRC temperature minimum (CBTmin) are shown. The rectangle
Melatonin PRC
2 DLMO 2 represents a period of 7.5 hours of sleep. The PRC curves of light
Advance

and melatonin are approximately out of phase. From Eastman CI,

Burgess HJ: How to travel the world without jet lag. Sleep Med Clin
1 1 2009;4:241255.
Phase shift (h)

0 0

1 1
Hypothesized
Delay

dead zone
2 2

3 3
12 15 18 21 0 3 6 9 12
Clock time

9 6 3 0 3 6 9 12 15
Hours before and after the dim light melatonin onset (DLMO)
time of melatonin or bright light

HUMAN PHASE REPONSES CURVES TO DIFFERENT FIGURE 2613 PRCs for different doses of exogenous
DOSES OF MELATONIN melatonin. Note that for the higher dose of melatonin,
3 3 the maximal effect was noted at an earlier time
3 mg
DLMO compared with the DLMO. The rectangle illustrates a
Phase shift with 3.0 mg melatonin (h)
Phase shift with 0.5 mg melatonin (h)

CBTmin
2 typical sleep period with core body temperature
Advance
Advance

0.5 mg minimum (CBTmin) shown in the last half of the sleep

0.5
period. From Eastman CI, Burgess HJ: How to travel the
1
world without jet lag. Sleep Med Clin 2009;4:241255.

0 0

1
Delay
Delay

0.5
2

1.0 3
12 15 18 21 0 3 6 9 12
Clock time

9 6 3 0 3 6 9 12 15
Hours before and after the dim light melatonin onset (DLMO)
time of taking melatonin pill

between the DLMO and the CBTmin (endogenous melato- melatonin administration is often not used in the early
nin already high). The cross-over point for melatonin (tran- morning because any hypnotic effects would not be well
sition from phase advance to phase delay) is during the night tolerated outside of a research setting. An exception is when
but may not precisely coincide with CBTmin. In addition, morning sleep is desired by a person working a night shift.
the shape of the melatonin PRC appears to depend on the
dose of melatonin studied and the method of determination Summary of Effects of Light and Melatonin
of the PRC (Fig. 2613). Note that the timing of the maximum A summary of the effects of bright light and melatonin is
phase delay induced by melatonin is several hours after the presented in Figure 2614 with illustrations of the use of
CBTmin. Thus, taking melatonin 1 or 2 hours after spontane- these interventions in two circadian rhythm sleep disorders
ous awakening causes the most phase delay. However, (CRSDs). Bright light in the evening causes a phase delay and
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524 Chapter 26 Circadian Rhythm Sleep Disorders

in the early morning a phase advance. Melatonin in the early
evening causes a phase advance and in the early morning a
phase delay. A simple description of the effects of light and
melatonin is that bright light pushes and melatonin pulls
the circadian rhythms. In this figure, it is assumed that the
CBTmin lies within the initial sleep period of the advanced
sleep phase disorder (ASPD) and the delayed sleep phase
disorder (DSPD) patients.
GENOMICS OF CRSD
The intrinsic 24-hour rhythm in the SCN neurons is due to
the interactions of a number of genes.27,28 These genes form
6P Midnight 6A Noon
Normal
S ASPD M upstream of a gene in a promoter region. The translational
M DSPD
S Light pushes M Melatonin pulls
FIGURE 2614 Summary of effect of light and melatonin on the circadian phase. In
patients with the advanced sleep phase disorder (ASPD), melatonin in the late night/
early morning phase delays, and in patients with the delayed sleep phase syndrome
(DSPD), melatonin in the early evening phase advances. For light, the effects are
opposite with early evening light phase delaying and early morning light phase
advancing. Adapted from Barion A, Zee PC: A clinical approach to circadian rhythm sleep
disorders. Sleep Med 2007;8:566577.
autoregulatory feedback loops on transcription (DNA to
mRNA) and translation (mRNA to proteins) that drive the
cycling pattern. The feedback is provided by the protein
translational products that can either stimulate or repress
further gene transcription. A brief description of a few of the
many molecular mechanisms responsible for the 24-hour
cycle in transcription, translation, and posttranscriptional
protein metabolism that drives the rhythmic cycle of the
circadian clock genes follows (Fig. 2615 and Table 263).
By convention, small letters refer to genes and capital letters
refer to protein translational products. For example, tran-
scription and translation of clock results in production of the
protein CLOCK. The human forms of genes are denoted
with a preceding h (e.g., hper2).
Proteins CLOCK and BMAL1 (synthesized from clock
and Bmal1 genes) diffuse into the cytoplasm and associate
as heterodimers (CLOCK:BMAL1). These heterodimers
then return to the nucleus and bind the Ebox region of genes
Per1, Per2, Cry1, and Cry2 and promote transcription of
these genes. Ebox is a DNA sequence that usually lies
products PER and CRY proteins are negative regulators that
S
turn off their own synthesis. The heterodimer PER:CRY and
homodimer CRY:CRY diffuse back into the nucleus, inhibit-
ing transcription of the associated genes. That is, PER:CRY
and CRY:CRY repress the CLOCK:BMAL1-driven transcrip-
tion of Pers and Crys. The synthesis of PER and CRY is under
the influence of CLOCK:BMAL1 and can occur only when
the level of intranuclear PER and CRY is low enough (after
degradation of these proteins). A number of other processes
alter these molecular events because PER and CRY can be
phosphorylated by several enzymes including casein kinase
1 epsilon (CK1), resulting in the ultimate degradation of the

Pers = Per1 or Per2 C CLOCK CRY CRY

Crys = Cry1 or Cry2 B BMAL1 PER PER

C
B
Clock Clock
C B
Bmal1 Bmal1 PER CRY
C B Nucleus  C B
E Pers PER CRY
E Pers
C B  C B
E Crys E Crys
Cytoplasm

CLOCK: BMAL1 heterodimer binds PER and CRY heterodimers and CRY
to Ebox enhancer resulting in increased homodimers suppress CLOCK and BMAL1
transcription of Pers and Crys genes driven transcription of Pers and Crys

FIGURE 2615 A schematic of molecular mechanism controlling the circadian clock. Some proteins are inducers of gene transcription,
and others inhibit transcription. Adapted from Vitaterna MH, Pinto LH, Turek FW: Molecular genetic basis for mammalian circadian
rhythms. In Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 4th ed. Philadelphia: Elsevier Saunders, 2005,
pp. 335350.
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 Chapter 26 Circadian Rhythm Sleep Disorders 525

TABLE 263 BOX 265

Circadian Clock Genes Circadian Rhythm Sleep Disorders
GENES PROTEIN 1. CRSDDelayed Sleep Phase Type, Delayed Sleep Phase
Circadian Locomotor Clock CLOCK Disorder (DSPD)
Output Cycles Kaput 2. CRSDAdvanced Sleep Phase Type, Advanced Sleep
Phase Disorder (ASPD)
Brain and muscle Bmal1 BMAL1
3. CRSDIrregular Sleep-Wake Type, Irregular Sleep-Wake
ARNT-like 1
Rhythm (ISWR)
Period per1, per2, per3 PER 4. CRSDFree-Running Type (FRT), Non-entrained Type
(non24-hr Sleep-Wake Syndrome, Free-Running Sleep
Timeless tim TIM
Disorder)
Cryptochrome cry1 and 2 CRY 5. CRSDJet Lag Type, Jet Lag Disorder
GENETIC POLYMORPHISMS 6. CRSDShift-Work Type, Shift-Work Disorder (SWD)
7. CRSD Due to Medical Condition
CRSD
8. Other CRSD Not Otherwise Specified (NOS)
DSPD hPer3 and Arylalkylamine 9. Other, CRSD Due to Drug or Substance
N-acetyltransferase genes From American Academy of Sleep Medicine: ICSD-2 International
ASPD hPer2 Phosphorylation site Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
mutation causes reduced
degradation of PER
(shortening the circadian
period)
Noon 6P Midnight 6A Noon
ASPD = advanced sleep phase disorder; CRSD = circadian rhythm sleep
disorder; DSPD = delayed sleep phase disorder.
Normal
ASPD
DSPD
BOX 264
FRSD
General Diagnostic Criteria for Circadian Rhythm
Sleep Disorder FRSD

A. There is a persistent or recurrent pattern of sleep FRSD

disturbance due primarily to one of the following:
i. Alterations of the circadian timing system.
ii. Misalignment between endogenous circadian rhythm
and exogenous factors that affects timing or duration
of sleep.
B. The circadian-related sleep disruption leads to insomnia,
excessive sleepiness, or both.
C. The sleep disturbance is associated with impairment of
social, occupational, or other areas of functioning.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
protein. The metabolism of PER and CRY influences the
stability and rate of entry of protein dimers or heterodimers
into the nucleus.
CIRCADIAN RHYTHM SLEEP DISORDERS
The International Classification of Sleep Disorders, second
edition (ICSD-2), lists criteria for a CRSD (Box 264).1 There
must be alteration of the circadian timing system, usually a
misalignment between endogenous circadian rhythm and
exogenous factors, that affects the timing or duration of
sleep. The alteration in circadian timing must lead to a sleep
complaint (insomnia, excessive sleepiness, or both). Finally,
ISWR
Work SWD
FIGURE 2616 Schematic diagram of several circadian rhythm sleep disorders.
The rectangles represent the timing of sleep. ASPD = advanced sleep phase disorder;
DSPD = delayed sleep phase disorder; FRSD = free-running sleep disorder; ISWR =
irregular sleep-wake rhythm; SWD = shift-work disorder. Adapted from Lu BS, Zee PC:
Circadian rhythm sleep disorders. Chest 2006;130:19151923; and Barion A, Zee PC:
A clinical approach to circadian rhythm sleep disorders. Sleep Med 2007;8:566577.
the change in wake-sleep must be associated with impair-
ment including social or occupation functioning. For
example, if a persons normal sleep phase is quite delayed but
is something that they desire, this would not be a CRSD.1
The ICSD-2 lists nine CRSDs (Box 265). A large propor-
tion of normal individuals experience problems with sleep
or alertness secondary to shift work or jet lag at some point
in their lives. The boundary between what constitutes a
normal response and what constitutes a disorder is blurry in
some disorders such as the shift-work disorder. A schematic
of the changes in the habitual sleep period is illustrated in
Figure 2616.
Comprehensive reviews of the existing evidence for eval-
uation and treatment of these disorders and practice param-
eters for evaluation and treatment of CRSD were published
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526 Chapter 26 Circadian Rhythm Sleep Disorders
BOX 266
Morningness-Eveningness Questionnaire,
Sleep Logs, and Actigraphy in Circadian Sleep
Rhythm Disorder
MEQ
AASM Practice Parameters: Insufficient evidence to
recommend
MEQ SCALE
Definitely morning type 7086
Moderately morning type 5969
Moderately evening type 3141
Definitely evening type 1630
SLEEP LOGS
Indicated in assessment of patients with suspected CRSD
(Guideline)
ACTIGRAPHY
Indicated to assist in evaluation of patients suspected of
CRSD (Guideline)
Useful as an outcome measure in evaluating the response
to treatment of CRSD (Guideline)
AASM = American Academy of Sleep Medicine; CRSD = circadian rhythm
sleep disorder; MEQ = morningness-eveningness questionnaire.
by the American Academy of Sleep Medicine (AASM) in
2007.2931 In evaluating patients for suspected CRSD, the
physician utilizes history, a sleep log for at least 7 days, and
often actigraphy (Box 266). The morningness-eveningness
questionnaire (MEQ) is discussed in the following section.
The MEQ and markers of circadian phase (DLMO) are used
for research studies but the clinical utility for routine evalu-
ation remains to be documented. Polysomnography is not
indicated for evaluation of patients with CRSD unless
another sleep disorder such as sleep apnea is suspected.
Morningness-Eveningness Questionnaire
The MEQ was developed by Horne and Ostberg in 1976.32
The MEQ contains 19 questions aimed at determining the
natural propensity to perform certain activities during the
daily temporal span. Most questions are framed in a prefer-
ential manner and require a response to specific times that
an individual would prefer to do a certain activity (as opposed
to when they actually do it). Each question has answers 0 to
6. The sum ranges from 16 to 86. Lower values correspond
to evening types (see Box 266).
Sleep Logs and Actigraphy
The AASM practice parameters state that sleep logs and
actigraphy are indicated for evaluation of patients with sus-
pected or known CRSD31 (see Box 266). Figure 2616 is a
schematic diagram of changes in the sleep period with the
different CRSDs compared with normal. In general, sleep
BOX 267
Circadian Rhythm Sleep DisorderDelayed
Sleep Phase Type (Delayed Sleep Phase
Disorder)Diagnostic Criteria
A. Delay in major sleep period in relation to desired sleep
time and wakeup time
a. Chronic or recurrent complaint of inability to fall
asleep at a desired conventional clock time.
b. Inability to awaken at a desired socially accepted
time.
B. When allowed to choose preferred schedule, patients
have normal sleep quality and duration for age and
maintain a delayed but stable phase of entrainment to
the 24-hour sleep-wake pattern.
C. Sleep log or actigraphy monitoring (including sleep
diary) for at least 7 days demonstrates a stable delay in
the timing of the habitual sleep period.
Note: In addition, a delay in the timing of other circadian
rhythms, such as the nadir of the core body temperature
rhythm, or DLMO, is useful for confirmation of the delayed
sleep phase.
D. The sleep disturbance is not better explained by another
current sleep disorder, medical or neurologic disorder,
mental disorder, medication use, or substance use
disorder.
DLMO = dim light melatonin onset.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
logs or actigraphy documents a habitual sleep period com-
pared with normal that is advanced (ASPD), delayed (DSPD),
progressively delayed (FRD), irregular (irregular sleep wake
rhythm [ISWR]), or with a daytime major sleep episode
(shift-work disorder).
Delayed Sleep Phase Disorder
Patients with the DSPD complain of inability to fall asleep at
a socially acceptable timea type of sleep-onset insomnia.
If allowed to maintain their own chosen schedule, they
would usually sleep for a fairly normal duration and feel
rested on arising.1,16,17,33 However, because of societal pres-
sures, they must awaken earlier than desired and are often
sleepy during the day. Therefore, they complain of difficulty
waking up and daytime sleepiness (short sleep duration). In
contrast to behaviorally induced sleep delay, these patients
cannot fall asleep earlier unless very sleep-deprived. Practice
parameters for the evaluation and treatment of DSPD have
been published (Box 267 and Table 264).
Epidemiology
The DSPD is the most common CRSD seen in sleep clinics.
DSPD is more common in adolescents and young adults
with an incidence of 7% to 16% in this population. The inci-
dence in the general population is unknown. Patients with
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 Chapter 26 Circadian Rhythm Sleep Disorders 527

TABLE 264 DSPD make up about 10% of patients seen in insomnia

Recommendations for Evaluation and Treatment clinics. The mean age of onset of DSPD is about 20 years.
of Delayed Sleep Phase Disorder
Pathophysiology
TOOLS RECOMMENDATION
A family history is present in about 40% of patients with
EVALUATION DSPD.1 The DSPD has been associated with genetic poly-
PSG Not routinely indicated (S) morphism in circadian clock gene hPer3,3,34 AA-NAT,35
and the clock gene. Another possibility would be an intrinsi-
MEQ Insufficient evidence (O)
cally long tau. Exposure to bright light in the evening
Circadian phase markers Insufficient evidence (O) (causing phase delay) or decreased exposure to morning
Actigraphy for diagnosis Indicated (G) light can exacerbate the problem.
Actigraphy for response Indicated (O)
Sleep Logs and Actigraphy
to therapy
Sleep logs (Fig. 2617) and actigraphy (Fig. 2618) typically
Sleep log Indicated (G) document a stable delay in the period relative to clock time
THERAPY with a typical sleep-onset time from 1 to 6 AM with wake
times in the late morning or early afternoon (10 AM2 PM).
Planned sleep schedule Indicated (O)
During the work week or school, a forced awakening will
Timed light exposure Indicated (G) cause a short sleep period.
Timed melatonin Indicated (G) On the weekend or nonschool or nonwork days, longer
sleep until late morning/early afternoon is noted. The Horne-
Hypnotics Not recommended (O)
Ostberg questionnaire (morning-evening preference) shows
Stimulants a night owl preference (eveningness). The DLMO is delayed
Alerting agents in patients with DSPD (see Fig. 266). As expected, the
(S) = standard > (G) = guideline > (O) = option; insufficient evidence;
CBTmin is also quite delayed. Some studies found the body
MEQ = morningness-eveningness questionnaire; PSG = polysomnography. temperature nadir in DSPD patients to occur earlier during
From Morgenthaler TI, Lee-Chiong T, Alessi C, et al: Practice parameters for the sleep period than that of normal individuals.36,37 For
the clinical evaluation and treatment of circadian rhythm sleep disorders.
Sleep 2007;30:14451459.
example, Watanabe and coworkers37 found the CBTmin
occurred near the middle of the nocturnal sleep period in
patients with DSPD in contrast to normal controls in whom

PM Midnight AM Noon PM
6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6

Sun X Mon

Mon X Tues

Tues X Wed

Wed X Thurs

Thurs X Fri

Fri X Sat

Sat X Sun

Sun X Mon

Mon X Tues

X Lights out - trying to sleep Asleep In bed Out of bed

FIGURE 2617 A sleep log from a patient with DSPD. Note the stable delay in sleep-onset time despite attempts to fall
asleep earlier on some nights. On the weekends, sleep continues until the late morning. Note that once the patient is asleep,
few awakenings are noted.
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528 Chapter 26 Circadian Rhythm Sleep Disorders

00:00 06:00 12:00 18:00 00:00 06:00 12:00 18:00 00:00

Thu/Fri
Fri/Sat
Sat/Sun
Sun/Mon
Mon/Tue
Tue/Wed
Wed/Thu
Thur/Fri

FIGURE 2618 An actigraph recording of sleep-wake activity, recorded using wrist activity monitoring, from an individual with DSPD. The individual goes to sleep around 5
to 6 AM and wakes between 12 and 1 PM each day. Note that all actigraphy data are double-plotted. A period of 48 consecutive hours is shown on each line. The last 24 hours
(second half) of each line is then repeated as the first 24 hours (first half) of the following line (00:00 is midnight). From Barion A, Zee PC: A clinical approach to circadian rhythm
sleep disorders. Sleep Med 2007;8:566577.

TABLE 265 In one study, an initial 2-week trial of light therapy at

Treatment for Delayed Sleep Phase Disorder 2500 lux given for 2 hours between 6:00 AM and 9:00 AM in
Light 250010,000 lux 30 min2 hr.
combination with evening light restriction demonstrated an
therapy Timing = at or slightly (1 hr) before advancement of CBTmin of 1.4 hours and an improvement
spontaneous wake time (ad lib sleep). in multiple sleep latencies.40 A later study reported a 1.5-
Light administered 12 1 hr earlier each day hour earlier sleep-onset time after 5 days of 3 hours of pho-
(use alarm if needed). Patient also typically totherapy given 1.5 hours after CBTmin.41
goes to bed earlier. The optimal timing, dose, and duration of bright light for
Restrict light in the evening. treatment of DSPD have not been defined but common rec-
Melatonin 0.33.0 mg given 57 hr before habitual ommendations are 2500 to 10,000 lux in the morning for 1
sleep-onset time to 2 hours. However, a pitfall of this approach is that light
35 hr before DLMO. may be administered on the wrong side of the temperature
Large melatonin dose has hypnotic effects. minimum. For example, if a patients habitual wake time is
DLMO = dim light melatonin onset. 11:00 AM, the CBTmin could be around 8 to 9 AM. Therefore,
exposure to bright light at 6 to 8 AM would induce a phase
delay in this individual.
it occurred in the last third of the sleep period. However, A practical approach for light therapy in DSPD (see Table
other investigators did not find a different relationship 265) is to start the light treatment at 1 or 2 hours before the
between CBTmin and sleep period.38 Differences in study unconstrained habitual awakening time with a light inten-
results may be due to different total sleep times and study sity of 2500 to 10,000 lux for 30 minutes to 2 hours (if pos-
designs. sible) and advance the light treatment 1 2 to 1 hour daily (with
alarm clock if needed).42 It is best to estimate the habitual
Treatment of DSPD awake time (and CBTmin) using ad lib sleep on the week-
Treatments for DSPD include (1) chronotherapy (a type of ends. In fact, starting treatment on the weekends may allow
sleep scheduling), (2) morning bright light, and (3) evening appropriate light exposure at a later clock time than permit-
melatonin (Table 265). Chronotherapy is a prescribed pro- ted during the school/work week. Once light treatment
gressive delay in bedtime until the desired sleep schedule is begins, the patient attempts to go to bed about 1 2 to 1 hour
reached.39 Basically, bedtime is delayed around the clock earlier each night. Once appropriate timing is reached, light
until it reaches an appropriate time.39 However, this treat- treatment 1 to 2 days a week could be used for mainte-
ment approach is not practical for most patients. Morning nance. It is also useful to restrict light in the evening hours
bright light and evening melatonin have both been used to (avoid phase delay).
phase advance the circadian rhythms in DSPD patients. The Various doses and timing of melatonin have also been
AASM standards of practice parameters state that chrono- used to treat DSPD.38,43 The goal is to give melatonin before
therapy may be effective (Option) and that morning light DLMO to phase advance. Mundey and colleagues38 used
exposure and properly timed evening melatonin are indi- both 0.3 and 3.0 mg of melatonin and found the magnitude
cated to treat DSPD (Guideline)31 (see Table 264). The prac- of phase advance correlated with the time of administration
tice parameters state that the optimal dose and timing of (earlier better). Of note, in this study, melatonin treatment
light have not been determined. in DSPD had a greater effect on wake time than sleep-onset
DaneshGroup.com

time.38 In another study, 5 mg of melatonin administered 5
hours before the DLMO was effective.43 However, larger
doses of melatonin are more likely to also have a hypnotic
effect. Current reasonable recommendations are to
administer 0.3 to 5.0 mg of melatonin 2 to 3 hours before
DLMO or 5 to 7 hours before habitual sleep time. One
could make a case for using melatonin 0.3 to 0.5 mg to pos-
sibly minimize hypnotic effects if sleepiness at the time of
administration is not desirable (see Table 265). There is
some evidence that use of the combination of light and mel-
atonin may be more effective at inducing a phase advance
than either used alone.44 Side effects of melatonin include
headache, dizziness, nausea, and drowsiness. At high doses,
melatonin may alter sex hormones.6 For this reason, some
clinicians are hesitant to use the medication long term in
adolescents or children.
Advanced Sleep Phase Disorder
The ASPD is thought to be quite rare if diagnostic criteria
are strictly followed. Advanced related sleep complaints, par-
ticularly early awakening, are more common. Often, patients
are able to stay awake but are unable to stay asleep. As a
consequence, classic ASPD is fairly rare but early morning
awakening is much more common. ASPD is associated with
aging, and nonaging ASPD is rare. Early morning awakening
can also be noted in depression.
Epidemiology
The prevalence of ASPD is not well documented but believed
to be about 1% in middle-aged populations and increases
with age. Men and women are equally affected.
Pathophysiology
Familial ASPD has been described with a mutation in the
circadian clock gene hPer2.45,46 However, other familial cases
do not show this pattern. Causes of ASPD include a short
endogenous circadian period or a dominant phase advance
region to light. In elderly patients who take early morning
walks, this behavior tends to phase advance.
Diagnosis
The ICSD-2 criteria (Box 268) require that the sleep period
be advanced with respect to the desired sleep time and
wakeup times. The use of a sleep log or actigraphy for at least
7 days is required to document a stable advance in the
normal sleep period. These patients complain of not being
able to stay awake in the evening for desired activities and
then early morning awakening.47 The differential diagnosis
includes poor sleep hygiene (evening or afternoon naps),
caffeine abuse, alcohol, and depression (can cause early
morning awakening).
Morningness-Eveningness Questionnaire
Patients with ASPD when completing the MEQ (Horne-
Ostberg questionnaire)32 record answers consistent with
morning type.
Chapter 26 Circadian Rhythm Sleep Disorders 529
BOX 268
Circadian Rhythm Sleep DisorderAdvanced
Sleep Phase Type (Advanced Sleep Phase
Disorder)Diagnostic Criteria
A. Advance in the major sleep period in relation to desired
sleep time and wakeup time
i. Chronic or recurrent inability to remain awake until a
desired conventional clock time.
ii. Inability to remain asleep until a desired socially
accepted time.
B. When allowed to choose preferred schedule, patients
have normal sleep quality and duration for age and
maintain an advanced but stable phase of
entrainment to the 24-hour sleep-wake pattern.
C. Sleep log or actigraphy monitoring (including sleep
diary) for at least 7 days demonstrates a stable advance
in the timing of the habitual sleep period.
Note: In addition, an advance in the timing of other
circadian rhythms, such as the nadir of the core body
temperature rhythm, or DLMO, is useful for confirmation of
the advanced sleep phase.
D. The sleep disturbance is not better explained by another
current sleep disorder, medical or neurologic disorder,
mental disorder, medication use, or substance use
disorder.
DLMO = dim light melatonin onset.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Sleep Logs and Actigraphy
Patients with ASPD demonstrate a stable advance in sleep
period with sleep onset 6 PM to 9 PM and awakenings from
2 AM to 5 AM (Fig. 2619).
Core Body Temperature, Dim Light Melatonin Onset
Circadian phase makers in ASPD patients demonstrate
advanced timing (Table 266).
Treatment
Chronotherapy (sleep schedule) can be used with a progres-
sive phase advance around the clock until the desired bedtime
is reached.48 For most patients, this is not practical. The most
common treatment is bright light in the evening from 7 to 9
PM (Table 267 and Boxes 269 and 2610). In one study,
4000 lux was administered for 11 consecutive days then
twice weekly for a 3-month period (maintenance).49 Unfor-
tunately, patients have difficulty complying with this treat-
ment plan. The AASM practice parameters mention evening
light as an Option for ASPD (see Table 267).31 Another
important form of light therapy is to AVOID early morning
light, which tends to cause a phase advance. Although early
morning melatonin would be a potential treatment (phase
delay), this is not practical and may not be safe if individuals
have to function in the morning. Melatonin has sedative
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530 Chapter 26 Circadian Rhythm Sleep Disorders

FIGURE 2619 A typical sleep log for a PM Midnight AM Noon PM

patient with ASPD. This illustrates an early 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6
bedtime and an early rise time. The patient
takes naps, which may exacerbate early Sun X Mon
morning awakening by decreasing sleep load.
Mon X Tues

Tues X Wed

Wed X Thurs

Thurs X Fri

Fri X Sat

Sat X Sun

X Lights out - trying to sleep Asleep In bed Out of bed

TABLE 266 TABLE 267

Changes in Sleep Pattern in Familial Advanced Recommendations for Evaluation and Treatment
Sleep Phase Disorder Compared with Controls of the Advanced Sleep Phase Disorder
FAMILIAL DIFFERENCE TOOLS RECOMMENDATION
CONTROL ASPD (MIN) EVALUATION
Sleep onset 23:10 0:40 19:25 1:44 3:45 PSG Not routinely indicated (S)
Sleep offset 7:44 1:13 04:18 2:00 3:25 MEQ Insufficient evidence (O)
DLMO 21:21 0.28 17:31 1:49 3:50 Circadian phase markers Insufficient evidence (O)
CBTmin 03:35 1:33 23:22 2:55 4:13 Actigraphy for diagnosis Indicated (G)
ASPD = advanced sleep phase disorder; CBTmin = core body temperature
minimum; DLMO = dim light melatonin onset.
Actigraphy for response Indicated (O)
Data from Jones C, Campbell S, Zone S, et al: Familial advanced sleep phase to therapy
syndrome: a short-period circadian rhythm variant in humans. Nat Med
1999;5:10621065. Sleep log Indicated (G)
Adapted from Auger RR: Advanced related sleep complaints and advanced THERAPY
sleep phase disorder. Sleep Med Clin 2009;4:219227.
Planned sleep schedule Indicated (O)
Timed light exposure Indicated (O)
effects especially at higher doses and during periods when Timed melatonin Indicated (O)
the endogenous melatonin is not elevated. However, timed
Hypnotics
melatonin was listed as indicated (Option) for treatment of
ASPD in the AASM practice parameters for CRSD.31 Stimulants
Alerting agents
CRSDIrregular Sleep-Wake Type (S) = standard > (G) = guideline > (O) = option; no recommendation due
to lack of evidence; MEQ = morningness-eveningness questionnaire; PSG =
The CRSDirregular sleep-wake type (also known as irreg- polysomnography.
From Morgenthaler TI, Lee-Chiong T, Alessi C, et al: Practice parameters for
ular sleep-wake rhythm [ISWR]) is characterized by lack of the clinical evaluation and treatment of circadian rhythm sleep disorders.
a clearly defined circadian rhythm of sleep and wake behav- Sleep 2007;30:14451459.
ior. Typically, sleep and wake periods are interspersed
throughout the day.1

Epidemiology outside light, exercise, and social activities. Some patients

The prevalence of ISWR is unknown. The disorder occurs
most frequently in institutionalized elderly patients with
dementia or institutionalized young patients with mental
retardation. Precipitating factors include poor sleep hygiene
and limited exposure to synchronizing zeitgebers including
may have a decrease in the circadian amplitude of the SCN-
alerting signal. In others, absence of zeitgebers (decreased
light and activity) may be important. Important risk factors
for ISWR include age, living in an institutional setting, and
dementia or mental retardation (Alzheimers disease).50
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BOX 269
Treatment of Advanced Sleep Phase Disorder
Sleep schedule (chronotherapy)progressive phase
advance.
Light
Bright evening light 79 PM.
Avoid light after temperature minimum (early morning
light).
Melatonin
Early AM melatonin potentially effective but sedative
effects make this impractical for most patients. Consider
a low dose to attempt to minimize sedative effects.
BOX 2610
Circadian Rhythm Sleep DisorderIrregular
Sleep-Wake TypeDiagnostic Criteria
A. There is a chronic complaint of insomnia, excessive
sleepiness, or both.
B. Sleep logs or actigraphy monitoring (including sleep
diaries) for at least 7 days demonstrates multiple
irregular sleep bouts (at least three) during a
24-hour period.
C. Total sleep time per 24 hours is essentially normal for
age.
D. The sleep disturbance is not better explained by another
current sleep disorder, medical or neurologic disorder,
mental disorder, medication use, or substance use
disorder.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Etiology
Factors involved in ISWR:
1. Abnormal circadian regulation
i. Damage or deterioration of the activity of the SCN.
ii. Diminished response to entraining agents such as
light.
2. Behavioral and environmental factors
i. Decreased exposure to bright light.
ii. Decreased physical activity and social activities.
iii. Poor sleep habits.
Sleep Logs and Actigraphy
Monitoring with actigraphy for at least 7 days demonstrates
multiple irregular sleep bouts (at least three) during a
24-hour period (Fig. 2620). The total sleep time is normal
for age. The AASM practice parameters for CRSD state that
actigraphy is indicated in ISWR for diagnosis and assessing
response to treatment.
Diagnosis of ISWR
Diagnosis requires a complaint of daytime sleepiness or
insomnia (although the caregiver rather than the patient
may complain). Actigraphy or sleep log for at least 7 days
Chapter 26 Circadian Rhythm Sleep Disorders 531
Day 1 Day 2
Day 2 Day 3
Day 3 Day 4
Day 4 Day 5
Day 5 Day 6
24 12 24 12 24
FIGURE 2620 Actigraphy shows an irregular pattern of wake and sleep in a nursing
home patient with dementia. Note that much of the sleep occurred during the day.
At least three episodes of sleep were noted during each 24 hours. This is a double plot.
Each line is 48 hours. The last 24 hours on one line is repeated as the first 24 hours on
the next line.
demonstrates multiple sleep periods (at least three) within
24 hours with approximately a normal total amount of sleep
for age. For most patients with ISWR, the sleep log is prob-
lematic and this is one setting in which actigraphy is espe-
cially helpful. Some actigraph devices also record light
exposure, and decreased light exposure may be a predispos-
ing factor for ISWR.
Treatment of ISWR
Treatment of patients with ISWR aims at consolidating both
sleep and wake periods. Daytime light has been tried with
some benefit.51 Melatonin has not been found to be effective
in most studies.52 A large randomized, controlled trial by
Riemersma-ven der Lek and associates53 compared four con-
ditions (bright lightmelatonin, dim lightmelatonin, bright
lightplacebo, and dim lightplacebo) in a group of institu-
tionalized elderly patients (87% had dementia). The light
conditions included bright (1000 lux) or dim (300 lux) light
between 9 AM and 6 PM. The melatonin and placebo condi-
tions included administration of either placebo or 2.5 mg of
melatonin in the evening. Light had a modest benefit in
improving some cognitive and noncognitive symptoms of
dementia. Melatonin (without bright light) decreased the
sleep latency and increased total sleep time but impaired
mood. Bright light + melatonin did not impair mood but
decreased sleep latency and increased total sleep time. Thus,
melatonin should probably not be used alone in elderly
patients in similar settings. A combination of light and mela-
tonin might be effective. Conversely, melatonin has been
shown to be of benefit in some populations of younger devel-
opmentally delayed or mentally impaired individuals. A
study by Pillar and coworkers54 found that 4-week treatment
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532 Chapter 26 Circadian Rhythm Sleep Disorders

with melatonin 3 mg improved sleep duration from 5.9 to TABLE 268

7.3 hours and sleep efficiency from 69.3% to 88% in a group Recommendations for Evaluation and Treatment
of psychomotor-retarded children. of the Irregular Sleep-Wake Rhythm
Interventions to treat ISWR include bright light during
TOOLS RECOMMENDATION
the day, structured daytime activities (mixed modality treat-
ment), and decreased noise and nighttime light. Hypnotics EVALUATION
have also been used but are associated with side effects (falls PSG Not routinely indicated (S)
or sedation) in the elderly. The AASM practice parameters31
MEQ Insufficient evidence (O)
recommended bright light during the day and mixed-
modality therapy (societal activities). Melatonin was recom- Circadian phase markers Insufficient evidence (O)
mended only in younger patients with retardation but not Actigraphy for diagnosis Indicated (O)
for elderly nursing home patients (Option).
Actigraphy for response Indicated (O)
to therapy
CRSDFree-Running Type (Non24-Hour
Sleep log Indicated (G)
Sleep-Wake Syndrome)
THERAPY
The circadian rhythm sleep disorderfree-running type
Planned sleep schedule Mixed modality treatment
(CRSD-FRT) is characterized by a progressive delay in sleep indicated in elderly nursing
onset each day (Fig. 2621, Table 268, and Box 2611). home patients (G) and
There are periods of time when patients may complain of in patients with mental
insomnia, early morning awakening, and daytime sleepiness retardation (O)
depending on the relationship of the internal circadian
Timed light exposure Indicated (O)
rhythms and external time. These complaints occur when
circadian rhythm is out of phase with conventional sleep and Timed melatonin Indicated for certain populations
wake times. For example, when the CBTmin is during the Yes moderate to severe mental
day, there will be sleepiness during the day and insomnia at retardation (O)
Not recommended for elderly/
night. When the circadian phase is aligned with a normal
demented NH patients (O)
sleep-wake period, complaints may not be present. There is
a steady drift of the sleep period by 1 to 2 hours each Hypnotics
day.1,24 Stimulants
Alerting agents
Epidemiology
(S) = standard > (G) = guideline > (O) = option; no recommendation
Up to 50% of totally blind patients have non-entrained cir-
due to lack of evidence; MEQ = morningness-eveningness questionnaire;
cadian rhythms. About 70% have chronic sleep complaints. NH = nursing home; PSG = polysomnography.
Rarely, CRSD-FRT occurs in sighted individuals.55 It has also From Morgenthaler TI, Lee-Chiong T, Alessi C, et al: Practice parameters for
the clinical evaluation and treatment of circadian rhythm sleep disorders.
been described after head trauma.56 Note that there are some
Sleep 2007;30:14451459.
blind patients whose circadian system responds to bright
light even though they have no visual perception. Some

00:00 06:00 12:00 18:00 00:00 06:00 12:00 18:00 00:00

Tue/Wed
Wed/Thu
Thu/Fri
Fri/Sat
Sat/Sun
Sun/Mon
Mon/Tue
Tue/Wed
Wed/Thu
Thur/Fri
Fri/Sat
Sat/Sun

FIGURE 2621 Actigram shows progressive delay in sleep offset (blue line) with a parallel delay in sleep onset. This is characteristic of the CRSD free-running type.
DaneshGroup.com
Reproduced with permission from Barion A, Zee PC: A clinical approach to circadian rhythm sleep disorders. Sleep Med 2007;8:566577.
 Chapter 26 Circadian Rhythm Sleep Disorders 533

BOX 2611 TABLE 269

Circadian Rhythm Sleep Disorder Recommendations for Evaluation and Treatment
Free-Running Type (Non24-Hour Sleep of Circadian Rhythm Sleep Disorder
Syndrome)Diagnostic Criteria Free-Running Type

A. There is a complaint of insomnia or excessive daytime TOOLS RECOMMENDATION

sleepiness related to abnormal synchronization between EVALUATION
the 24-hour light-dark cycle and the endogenous
circadian rhythm of sleep-wake propensity. PSG Not routinely indicated (S)
B. Sleep log or actigraphy (with sleep diary) for at least 7 MEQ Insufficient evidence (O)
days demonstrates a pattern of sleep and wake times
that typically delay each day with a period time greater Circadian phase markers Insufficient evidence (O)
than 24 hours. Actigraphy for diagnosis Indicated (O)
Note: Monitoring or sleep logs for greater than 7 days is Actigraphy for response Indicated (O)
preferred to document a delay. to therapy
C. The sleep disturbance is not better explained by another Sleep log Indicated (G)
current sleep disorder, medical or neurologic disorder,
THERAPY
mental disorder, medication use, or substance use
disorder. Planned sleep schedule Indicated (O)
From American Academy of Sleep Medicine: ICSD-2 International
Timed light exposure Indicated (O)
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005. Timed melatonin Indicated sighted (O),
indicated unsighted (G)
Hypnotics
nonvisual function is still present in these patients with gan-
glion cells and RHT intact. Stimulants
Alerting agents
Pathophysiology (S) = standard > (G) = guideline > (O) = option; no recommendation due
In blind individuals, the absence of nonvisual light infor- to lack of evidence; MEQ = morningness-eveningness questionnaire; PSG =
mation to the SCN allows for the intrinsic phase delay to be polysomnography.
From Morgenthaler TI, Lee-Chiong T, Alessi C, et al: Practice parameters for
manifested. The cause of CRSD-FRT in sighted individuals the clinical evaluation and treatment of circadian rhythm sleep disorders.
is unknown. They may have a long circadian period (delay Sleep 2007;30:14451459.
is too large to be entrained by 1 2 hour phase advance from
light).
BOX 2612
Sleep Logs and Actigraphy Treatment in Patients with Circadian Rhythm
Sleep logs and actigraphy (see Fig. 2621) demonstrate a Sleep DisorderFree-Running Type
progressive phase delay in patients with CRSD-FRT. These
Blind individuals
demonstrate a progressive phase delay in the sleep period.
Melatonin 0.510 mg given 1 hour before desired
bedtime.
CBTmin and DLMO Maintenance dose once entrained is 0.5 mg of
There is a progressive delay in the CBTmin and the DLMO melatonin.
(see Fig. 266). If some light perception, can try AM light.
Treatment recommendations in sighted individuals are
Treatment of CRSD-FRT less clear
The treatment in blind patients includes melatonin of various Evening melatonin (phase advance).
doses before desired bedtime (Table 269 and Box 2612). Maximum daytime sun exposure (bright light after
In one study, 10 mg of melatonin was given 1 hour before CBTmin to phase advance).
desired bedtime (Fig. 2622). A maintenance dose of 0.5 mg Keep regular sleep-wake schedule.
of melatonin is used.57 In a few patients who failed to entrain CBTmin = core body temperature minimum.
on 10 mg of melatonin, there was success with a lower dose58
(see Table 269 and Box 2612). The treatment in sighted
patients may include both melatonin and appropriately maintain the CBTmin during the night. A fixed wakeup time
timed light exposure. Light is timed to oppose the intrinsic with daily light treatment could be used for maintenance.
progressive phase delay. That is, light should be timed several
hours after the CBTmin to induce a phase advance. One CRSDJet Lag Type
might begin treatment during a time when the CBTmin The jet lag type of CRSD is due to a temporary mismatch
occurs in the early morning (35 AM). The goal would be to between internal circadian rhythms (endogenous circadian
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534 Chapter 26 Circadian Rhythm Sleep Disorders

FIGURE 2622 A blind patient with free-running type (tau = 80

24.3 hr) was treated with 10 mg of melatonin about 1 hour before
60 0
preferred bedtime. The timing of the DLMO on sequential days is 24.3 hr
plotted (circles). Treatment was started when the DLMO was about 9 40
PM. Once entrained, the dose was slowly decreased every 2 weeks.
20 Start of 10 10 mg given 1 hour
Melatonin as low as 0.5 mg maintained entrainment. After treatment
treatment before preferred bedtime
stopped, the patient began to free-run again. Adapted from Lewy AJ, 0
10
Emens JS, Lefler BJ, et al: Melatonin entrains free-running blind people

Melatonin dose (mg/day)

20 10
according to a physiological dose response curve. Chronobiol Int 2005;
22:10931106. 8
40
Treatment 6 Dose decreased

Day
60 decreased 4 every 2 weeks
2
80
1
100 0.5
120
End of
140 treatment
0
160

180

200
0 12 24 12 24 12
Hour

BOX 2613 Pathophysiology

Circadian Rhythm Sleep DisorderJet Lag
TypeDiagnostic Criteria
A. There is a complaint of insomnia or excessive daytime
sleepiness associated with transmeridian jet travel
across at least two time zones.
B. There is associated impairment of daytime function,
general malaise, or somatic symptoms such as
gastrointestinal disturbance within 12 days after
travels.
C. The sleep disturbance is not better explained by another
current sleep disorder, medical or neurologic disorder,
mental disorder, medication use, or substance use
disorder.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
clock) and external clock time (sleep-wake pattern) required
by rapid change to a new time zone. There must be a
complaint of impairment of sleep and/or daytime func-
tion (Box 2613).
Epidemiology
The jet lag type of CRSD can occur in all ages but manifesta-
tions are worse in the elderly. Jet lag type is a product of our
society with approximately one-half million people in the air
at any moment worldwide. Aircrews are more vulnerable to
jet lag with frequent phase shifting. About one third of trav-
elers do not experience jet lag.
Jet lag begins after travel across at least two time zones.1,59
Desynchrony between body and local time zone is known
to cause problems with sleep, alertness, and performance.
The degree of dysfunction depends on (1) the number of
time zones crossed, (2) the direction of travel (westward
travel better tolerated), (3) sleep loss during travel, (4) avail-
ability of local time cues (exposure to natural light at
destinationdepends on weather, business schedule, and
other factors), and (5) ability to tolerate circadian misalign-
ment (decreases with age). Westward travel is better toler-
ated because the body is phase advanced compared with
local time. In general, it is easier to adapt (phase delay)
because of the intrinsic phase delay (tau >24 hr). In east-
ward travel, the body is phase delayed. It is more difficult
to undergo adaptation to the new time zone with a phase
advance. Sleep occurs normally on the rising phase of mela-
tonin rhythm and the falling phase of core temperature
rhythm. It is estimated that it takes about 1 day per hour of
time zone change to adjust (maximum adaptation is a
phase shift of 1 2 1 hr/day, depending on direction of
travel). In overnight flights, some degree of sleep loss is
inevitable. Flying first class (more room), wearing eye shades
or ear plugs, and possibly a hypnotic can minimize sleep
loss. If this is not possible, a short nap on arrival at the new
destination may help. Drinking adequate fluids and avoiding
alcohol may also help. The availability of exposure to natural
light in the new destination can be influenced by time of
year, weather, and schedule (indoor meetings, societal obli-
gations). The general recommendation is to eat on the des-
tination schedule.
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Antidromic Entrainment
Travel over six time zones may result in phase shifting in the
opposite direction of the direction of travel (i.e., adapting
the wrong way), so-called antidromic re-entrainment.
For example, eastern flight requires a phase advance to accli-
mate to the new time zone. However, after an eastward flight
across nine time zones, the travelers CBTmin normally at 5
AM in the old time zone would occur at 2 PM in the new time
zone. Thus, morning light in the new time zone would cause
phase delay because light exposure occurs before CBTmin.
Of note, some experts recommend that all flights that cross
more than 8 to 10 time zones be treated as if they were west-
ward travel (interventions target progressive phase delay).
Symptoms Associated with Jet Lag CRSD
Symptoms associated with jet lag may include (1) daytime
tiredness or impaired daytime alertness, (2) inability to get
to sleep at night (eastward flight), and (3) early awakening
(westward flight). Other symptoms may include disorienta-
tion; gastrointestinal problems (poor appetite), inappro-
priate timing of defecation (gut lag), excessive urination,
menstrual abnormalities (flight crew), inappropriate meta-
bolic responses (insulin and other hormones); and heart
disease. Symptoms may be worsened by stresses of airplane
travel itself or use of caffeine or alcohol.
Treatment of Jet Lag
A number of treatments for jet lag have been recommended
depending on the direction of travel (Tables 2610 to 2612).
Websites are available that allow the traveler to enter current
and future locations and a prescription is generated for inter-
ventions to minimize jet lag. One difficulty with providing
recommendations is in estimating the current CBTmin and
also that entrainment in the new destination may depend on
societal demands in the new time zone that preclude follow-
ing the prescription.
General sleep hygiene measures include a dark, quiet
sleep environment with earplugs or eye shades if needed. If
the plane flight is long, sleeping on the flight during appro-
priate hours (destination nighttime) may be helpful. In
general, daytime naps should be avoided at the destination.
New York
Noon 6P Midnight 6A Noon
Paris
6P Midnight 6A Noon 6P
6 time zones eastward
Flight D D S S S S
M S S S S
M SS S S
M S SS S
M SS SS
M SS S
D  dark S  sunlight or bright light M  melatonin
Chapter 26 Circadian Rhythm Sleep Disorders 535
However, napping can improve alertness for special demands
(e.g., giving a talk). Napping removes photic stimuli so
this can delay adaptation if napping occurs at a time when
light exposure would shift circadian rhythms in the correct
direction.
Eastward Flights The patient is phase delayed (a phase advance
is required) (Fig. 2623). One method is to phase advance 1
hour per day with bright light in the morning before travel
begins (Fig. 2624).60,61 At the new destination, morning
light should be sought (as long as it is after CBTmin). Evening
light should be avoided on arrival at the new destination (to
avoid phase delay). Melatonin before CBTmin might be
useful if the hypnotic effects would not interfere with wakeful
activities. Hypnotics can help with sleep but do not neces-
sarily help with alertness the next day.62 Even if the indi-
vidual gets adequate sleep, decreased circadian alertness will
occur at time of CBTmin. Stimulants (caffeine) may be
TABLE 2610
Jet Lag Facts
Typical internal 92 min/day delay on westward flights.
clock resetting 57 min/day advance on eastward
flights.
Eastern travel Difficulty falling asleepsleep-onset
insomnia.
May not notice sleep difficulty the
first night in new time zone if sleep
deprived (because sleep during
flight may have been poor).
Sleep fragmented, decreased REM
and stage N3 sleep.
Western travel Less persistent symptoms.
First night: sleep quality good early
in sleep period (deprivation).
Increased REM early in sleep period
as new bedtime falls nearer to prior
REM period.
Early awakenings
REM = rapid eye movement.
FIGURE 2623 Schematic of a flight from New York to Paris (6 time
zones eastward). Sleep times are shown as rectangles and the CBTmin
as blue triangles. On arrival, light is avoided (D) before CBTmin to
prevent phase delay and sunlight exposure is used after CBTmin to
produce a phase advance. Melatonin is taken at bedtime. The
circadian phase advances until the CBTmin is within the sleep period
(rectangle). However, this process takes several days. For simplicity,
timing of melatonin is kept constant.
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536 Chapter 26 Circadian Rhythm Sleep Disorders

TABLE 2611
Recommendations for Jet Lag
EASTWARD TRAVEL WESTWARD TRAVEL
Internal rhythm is phase delayed. Internal rhythm is phase advanced.
Adaptationphase advance. Adaptationphase delay.
BEFORE TRAVEL
Try to reset body clock to Shift sleep 12 hr earlier before trip Shift sleep 12 hr later before trip (bright
minimize necessary change. (bright light in AM). light in PM).
DURING TRAVEL
During flight. Sleep if possibleespecially on long Sleep if possibleespecially on long
flightsto avoid sleep loss. flightsto avoid sleep loss.
Sleep during time corresponding to night Sleep during time corresponding to night
in the destination if possible. in the destination if possible.
Drink adequate H2O, avoid alcohol. Drink adequate H2O, avoid alcohol.

ON ARRIVAL
Anticipated changes in sleep. Difficulty falling asleep. Difficulty staying asleep.
Difficulty waking up. Early awakening.
Appropriate light exposure. Seek morning light. Seek evening light.
If crossing more than eight For the first 2 days after arrival, avoid For 23 days, avoid bright light in the late
time zones, avoid light bright light for the first 23 hr after evening (at dusk); starting on the third
when it may inhibit dawn; starting on the third day, seek day, seek exposure to bright light in the
adaptation. exposure to bright light in the morning. evening.
Melatonin. Take 0.53 mg at local bedtime nightly Take 0.5 mg during the second half of the
until you adjust (phase advance). night (after CBTmin to phase delay).
Hypnotics. Consider taking at bedtime for a few days. Consider taking at bedtime for a few days.
Caffeine. Drink judiciously, avoid after midday. Drink judiciously, avoid after midday.
CBTmin = core body temperature minimum.
Adapted from Sack RL: Jet lag. N Engl J Med 2010;362:440447.

FIGURE 2624 The patient illustrated in Figure 2623 attempts New York
to reduce the time required for adaptation by use of a preflight Noon 6P Midnight 6A Noon
phase advance to minimize jet lag on arrival. There are fewer days
until the CBTmin (blue triangles) is within the desired sleep period
Baseline Pre-flight advance
(rectangles).
BL
Paris BL
6P Midnight 6A Noon 6P
6 time zones eastward

Flight D SSSS
M S SSS
M SS S S
M S SS S

BL  bright light D  dark S  sunlight or bright light M  melatonin

Sleep period (dark)

helpful to maintain alertness during the day in the new
locale. A recent study found that 150 mg of armodafinil (R
isomer of modafinil) increased wakefulness after eastward
travel through six time zones.63
Westward Flights The patient is phase advanced relative to
local time (a phase delay is required). One could try to phase
delay before travel begins (go to bed later, get up later) using
evening bright light for 1 to 3 hours. Light should be avoided
in the morning in the new destination (if it occurs soon after
CBTmin) to prevent phase advance. Exposure to light in the
evening (if before CBTmin) may be helpful (phase delay).
Melatonin at bedtime in the destination if taken before
CBTmin may have hypnotic action but induces phase shift
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 Chapter 26 Circadian Rhythm Sleep Disorders 537

TABLE 2612 BOX 2614

Recommendations for Evaluation and Treatment Circadian Rhythm Sleep DisorderShift-Work
of Jet Lag Type (Shift-Work Disorder)Diagnostic Criteria
TOOLS/TREATMENT RECOMMENDATION A. There is a complaint of insomnia or excessive daytime
EVALUATION sleepiness that is temporally associated with a recurring
work schedule that overlaps the usual time for sleep.
PSG Not routinely indicated (S)
B. The symptoms are associated with the shift-work
MEQ Insufficient evidence (O) schedule over the course of at least 1 month.
C. Sleep log or actigraphy monitoring (with sleep diaries)
Circadian phase markers Insufficient evidence (O)
for at least 7 days demonstrates disturbed circadian and
Actigraphy for diagnosis Not routinely indicated (O) sleep-time misalignment.
Actigraphy for response Not routinely indicated (O) D. The sleep disturbance is not better explained by another
to therapy current sleep disorder, medical or neurologic disorder,
mental disorder, medication use, or substance use
Sleep log Indicated (G) disorder.
THERAPY From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Planned sleep schedule Indicated (O) Westchester, IL: American Academy of Sleep Medicine, 2005.

Timed light exposure Indicated (O)

Timed melatonin Indicated (S)
Hypnotics Indicated (O)
Stimulants Indicated (O)
(S) = standard > (G) = guideline > (O) = option; MEQ = morningness-
eveningness questionnaire; PSG = polysomnography.
From Morgenthaler TI, Lee-Chiong T, Alessi C, et al: Practice parameters for
the clinical evaluation and treatment of circadian rhythm sleep disorders.
Sleep 2007;30:14451459.
in the wrong direction (phase advance). If melatonin is used,
it is recommended that a small dose (avoid prolonged hyp-
notic action) be taken during the last half of the night. Taking
melatonin on awakening while at the correct time for phase
delay may make the individual sleepy (counterproductive).
Hypnotics at bedtime can help with sleep but do not neces-
sarily help with alertness the next day. Even if the patients
gets adequate sleep, decreased circadian alertness will occur
at time of CBTmin. Stimulants (caffeine) may be helpful to
maintain alertness during the day in the new locale.
Crossing More than Eight Time Zones Exposure to light at the
wrong time should be avoided because this may occur on the
wrong side of CBTmin for appropriate adaptation. After east-
ward flights, avoid very early light (avoid inappropriate
phase delay); on westward flights, avoid light at dusk (avoid
inappropriate phase advance) for 2 to 3 days.59 Thereafter,
light at the usual times may help with adaptation. Conversely,
as noted previously, some physicians recommend attempts
at phase delay even if the direction of travel is eastward when
more than eight time zones are crossed.
Circadian Rhythm Sleep Disorder
Shift-Work Type
The circadian rhythm sleep disordershift work type1 is
characterized by excessive sleepiness or insomnia temporally
associated with recurring work schedule that overlaps the
usual time for sleep (Box 2614). The problem must last at
least 1 month. A sleep log or actigraphy for at least 7 days
documents circadian and sleep time misalignment. The
boundary between a normal and a pathologic response to
circadian stress of unnatural sleep schedule associated with
shift work remains unclear. The shift-work disorder is a
common problem in industrialized countries due to the need
for some occupations and services to continue to function
24 hours per day. The elements of diagnostic evaluation and
treatment recommended by the practice parameters of the
AASM are listed in Table 2613.31
Epidemiology
Up to 20% of the population in industrialized societies
works in an occupation requiring shift work. The total
number of night shift workers is 2% to 5% of the population.
About 5% to 10% of shift workers experience such signifi-
cant insomnia or sleepiness during the shift (or day) to
qualify for this disorder.
Risk Factors
Risk factors include advancing age, possibly women greater
than men, morning light exposure (long commute home or
morning social obligations, this inhibits adaptive phase
resetting). There are also limited data that morning types
(MEQ) tend to get shorter daytime sleep after a night shift
but further studies are needed.1
Pathophysiology
There are a number of exacerbating factors including long
shifts (fatigue) and the common practice of resuming normal
daytime activities and nighttime sleep on the weekends. The
sleepiness at night is often due not only to the accumulated
sleep load but, more importantly, to loss of the circadian
alerting signal.
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538 Chapter 26 Circadian Rhythm Sleep Disorders

TABLE 2613 Sleep Logs and Diaries

Recommendations for Evaluation and Treatment Sleep logs and diaries tend to document the altered routine
of Shift-Work Disorder and the effect on sleep.
TOOLS RECOMMENDATIONS
Circadian Markers
EVALUATION Little CBTmin data are available. Studies of DLMO suggest
PSG Not routinely indicated (S) that night workers are quite variable in their circadian adap-
tation. Of note, symptoms do not always correlate with
MEQ Insufficient evidence (O)
whether or not circadian adaptation has occurred.
Circadian phase markers Insufficient evidence (O)
Actigraphy for diagnosis Indicated (O) Night Shift Work
The daytime sleep in night shift workers is shorter than
Actigraphy for response Indicated (O)
normal (56 hr). The majority of workers do not have cir-
to therapy
cadian adaptation due to societal obligations. They typically
Sleep log Indicated (G) get light after their CBTmin on the drive home and, there-
THERAPY fore, phase advance. Bright light during the start of the shift
(before CBTmin) and avoiding light in the early morning
Planned sleep schedule Indicated (S)
(preventing phase advance) can potentially move CBTmin
Timed light exposure Indicated (G) to within the daytime sleep period.64 Scheduled naps before
Timed melatonin Indicated (G) or in the early part of the shift may improve alertness.65,66
Two-hour naps during late afternoon before the evening shift
Hypnotics Indicated (G)
are more effective than 2-hour naps during the shift. In a
Stimulants Indicated (O) (caffeine) simulated night shift study over five consecutive nights,
Alerting agents Indicated (G) Crowley and colleagues67 studied the effects of different
interventions and the effect on shifts in CBTmin and perfor-
(S) = standard > (G) = guideline > (O) = option; MEQ = morningness-
eveningness questionnaire; PSG = polysomnography. mance (Fig. 2625). The groups that shifted the tempera-
From Morgenthaler TI, Lee-Chiong T, Alessi C, et al: Practice parameters for ture minimum to within the normal sleeping hours had
the clinical evaluation and treatment of circadian rhythm sleep disorders.
improved nocturnal functioning on the psychomotor vigi-
Sleep 2007;30:14451459.
lance task (PVT). They used a combination of light during
the simulated shift, dark glasses during simulated drive
home, and melatonin before sleep. Of interest, the groups
with the latest CBTmin at baseline were the ones able to
completely entrain to the new schedule.67,68 Circadian phase

Psychomotor Vigilance Task

Worse
1200 CBTmin
Baseline After 5 nights
1000
Response time in ms

Non-entrained 4:21 5:37

800
Partially 5:12 10:53
re-entrained
600
Completely 7:13 13:48
re-entrained
400

200
Better 1 2 3 4 5

FIGURE 2625 Change in psychomotor vigilance task (PVT) over five consecutive simulated night shifts in groups non-entrained,
partially entrained, and completely re-entrained. The non-entrained group had a worsening in the PVT over five nights (increased
response time). The other two groups did not have a deterioration over the five night shifts. The time of core body temperature
minimum (CBTmin) is illustrated for each group at baseline and after five nights. The CBTmin shifted to within daytime sleep in the
two groups with better function. Subjects were given different combinations of bright light versus dim light during the simulated
night shift, dark glasses or normal sunglasses in the morning, and melatonin or placebo before sleep time. Adapted from Crowley SJ,
Tseng CU, Fogg LF, Eastman CI: Complete or partial re-entrainment improves performance, alertness, and mood during shift-work. Sleep
2004;27:10771087.
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was measured by DLMO with CBTmin = DLMO + 7 hours.
Melatonin given before morning sleep after a night shift
resulted in minimal change in total sleep time and added
little to circadian shifts induced by interventions with
light.68,69 One study found a significant phase advance with
melatonin in the early evening for patients who desire a
prolonged sleep period before the night shift.70
Sallinen and associates65 compared four nap strategies
(nap duration/timing: 50 min at 1 AM, 50 min at 4 AM, 30 min
at 1 AM, 30 min at 4 AM) to the no-nap condition using an
experimental night shift protocol. Napping improved reac-
tion time in the second half of the night. The early naps
produced increased alertness (assessed by polysomnography
sleep latency). In another study, Schweitzer and coworkers66
showed napping before the night shift, especially when com-
bined with caffeine, improved alertness as assessed with mul-
tiple sleep latency test (MSLT) and PVT. The alerting agent
modafinil (200 mg given at the start of the night shift) is U.S.
Food and Drug Administration (FDA) approved to improve
alertness during shift work.73 However, the medication did
not normalize alertness. Recently, armodafinil (the R enan-
tiomer of modafinil) was also demonstrated to be helpful in
maintaining alertness during shift work.72 Hypnotics have
also been used in an attempt to improve daytime sleep.
Walsh and colleagues73 found that use of triazolam increased
daytime sleep duration by about 50 minutes but did not
reduce circadian sleep tendency in the early morning hours.
Rotating Shifts
There is greater sleep loss with rapidly rotating shifts than
with slowly rotating shifts (slow = 3-wk periods). Clockwise
rotation is better tolerated than counterclockwise due to
natural tendency to phase delay.
Complications of Night Shifts
A number of complications of shift work have been proposed
including gastrointestinal disturbances (constipation/
diarrhea), obesity, miscarriage, drug dependency, and social
and family life disturbances.
Treatment of Shift-Work Disorder
The recommended treatments for shift-work disorder (SWD)
are listed in Table 2613 and Box 2615. Planned sleep
schedule (naps), timed bright light exposure, timed melato-
nin administration, stimulants (caffeine), and alerting agents
(modafinil) were also listed as indicated with various levels
of recommendation in the AASM circadian practice param-
eters.31 The goals of treatments include interventions to (1)
modify circadian rhythms to ameliorate symptoms of circa-
dian rhythm misalignment, (2) decrease sleep load during
the night (naps or hypnotics before daytime sleep), or (3)
increase alertness (caffeine or modafinil). Stimulants were
given the lowest level of recommendation, but evidence for
their efficacy is growing. There are actually less convincing
data for daytime melatonin than for stimulants. The ratio-
nale behind timed bright light exposure is the supposition
that having CBTmin closer to (or within) the daytime
Chapter 26 Circadian Rhythm Sleep Disorders 539
BOX 2615
Night Shift Treatment Recommendations
Bright light for 36 hr during the start of shiftphase
delay.
Short scheduled naps (preshift or during shift).
Avoid bright light on the way home in the AM (use dark
goggles if trip home is after sunrise to avoid phase
advances).
Quiet dark sleep environment at home during sleep.
Melatonin administered in the morning at bedtime
(hypnotic and phase delay effects).
Go to bed as soon as patient reaches home.
Stimulants/alerting agents at the start of the shift
Caffeine (250400 mg) during first 2 hours of night
shift.
Modafinil 200 mg (or armodafinil 150 mg) taken 3060
minutes before start of the night shift (FDA approved
for treatment of sleepiness in shift work)
Hypnotics before daytime sleepcan increase total sleep
time but do not help alertness at night.
FDA = U.S. Food and Drug Administration.
6P Midnight 6A Noon 6P
Sleep
S
A Work Sleep
L Sleep
L Sleep
L Sleep
L Sleep
B L Sleep
Core body temperature
minimum
FIGURE 2626 Interventions for night shift work. Top line, A normal sleep period
and CBTmin. A, Light and activity during the night work shift cause some phase delay.
However, light on the commute home opposes this process (causes phase advance).
B, CBTmin is shifted toward daytime sleep by using bright light (L) during the first part
of the work period (shift) and wearing dark goggles on the commute home. Note that
the duration of light during the night shift can increase as the CBTmin is progressively
delayed.
sleep period will improve sleep quality and amount (Fig.
2626). Patients should minimize light on the commute
home (dark goggles) if possible because this tends to phase
advance. In some studies, bright light at the start of the night
shift induced a beneficial phase delay.64,67,68 Bright light also
has a direct alerting effect. Melatonin has been used before
morning sleep after the night shift both for its soporific
effects and for its phase delaying effects (to delay CBTmin
into morning sleep time). However, Crowley and col-
leagues67,68 found no improvement in morning sleep or phase
delay with melatonin given at 8:30 AM (1.8 mg sustained
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540 Chapter 26 Circadian Rhythm Sleep Disorders

release). The soporific effects of melatonin were also not

CRSDNot Otherwise Specified
significant for sleep after night shift work.69 Another study
showed the phase shifting response to melatonin 0.5 mg CRSD Due to Drug or Substance
given at 800 to 1000 hours after the night shift to be variable The criteria for CRSD due to drug or substance include dis-
(compared with placebo), with only a minority of night orders that (1) satisfy criteria for a CRSD, (2) are due to a
workers having a phase shifting response.71 Of note, field drug or substance, and (3) do not meet criteria for other
studies of actual patients often show much smaller effects of circadian rhythm disorders.
either light or melatonin treatment on shift workers. For
example, one study using only 30 minutes of light exposure CLINICAL REVIEW QUESTIONS
or 3 mg of melatonin before bedtime showed small effects.72
In this study, melatonin added 15 to 20 minutes to daytime 1. A 25-year-old man has difficulty falling asleep until
sleep whereas bright light (short duration) had minimal 3 AM. On weekends, he sleeps until 10:30 to 11:00 AM.
effects. Napping either before the night shift or during the On work days, he uses an alarm clock to wake up at 7:00
AM but has difficulty getting out of bed and is sleepy
shift can be helpful.65,66 Short naps are preferred to decrease
sleep inertia. Stimulants at the start of the shift (caffeine, during the day. What time do you recommend light
modafinil, or armodafinil) may be helpful but do not com- therapy be initially administered?
pletely reverse the fall in alertness that occurs near the A. 6:00 AM.
CBTmin.66,73,74 A dark, quiet bedroom or hypnotics may help B. 7:00 AM.
daytime sleep. As previously noted, whereas use of hypnotics C. 8:00 AM.
can increase the duration of daytime sleep time, during the D. 10:00 AM.
day, they have not been shown to improve alertness in the
early morning hours during shift work.75 2. What is the average circadian period in humans?
A. 23.8 hr.
B. 24.0 hr.
CRSDDue to Medical Condition (Box 2616)
C. 24.2 hr.
Disorders Associated with CRSD D. 24.6 hr.
1. Dementiadecreased amplitude or absent circadian
rhythms. 3. A graph of core body temperature is shown in Figure
2. Movement disorders (Parkinsons disease). 2627. Bright light at which point (A, B, C, D, or E)
3. Blindness. results in the maximum phase advance?
4. Hepatic encephalopathy. 4. Which of the following is NOT true about photic input
to the SCN?
Treatment A. Photic information travels to the SCN via the RHT.
Treatment of underlying medical disorder may or may not
B. The major photosensors for entrainment of the SCN
improve the CRSD component.
are the rods and cones.
C. Light can entrain some blind individuals.
BOX 2616 D. The SCN pathway mediating inhibition of melatonin
travels through the superior cervical ganglion.
Circadian Rhythm Sleep Disorder
Due to Medical Condition
A E
A. There is a complaint of insomnia or excessive daytime
sleepiness related to alterations of the circadian D
time-keeping system or misalignment between 37.6
endogenous circadian rhythm and exogenous factors B
Body temperature (C)

C
that affect the timing or duration of sleep.
B. An underlying medical or neurologic disorder
predominantly accounts for the circadian sleep disorder. 37.0
C. Sleep log or actigraphy monitoring (with sleep diaries)
for at least 7 days demonstrates disturbed or low-
amplitude circadian rhythmicity.
D. The sleep disturbance is not better explained by another 36.4
current sleep disorder, medical or neurologic disorder,
mental disorder, medication use, or substance use
12 16 20 24 4 8 12
disorder.
Time of day
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual. FIGURE 2627 What should the timing of light be for maximum phase advance
Westchester, IL: American Academy of Sleep Medicine, 2005.
(A, B, C, D, E)?
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 Chapter 26 Circadian Rhythm Sleep Disorders 541

5. Point mutation in which gene has been associated with C. Measured with the subject in dim light.
ASPD? D. Typical threshold values are 3 pg/mL for salivary
A. Clock. and 10 pg/mL for plasma melatonin.
B. Time.
12. A patient with the delayed sleep phase syndrome has a
C. hPer2. typical wake time on the weekends of 1 PM. He typically
D. Alarm. has to awaken at 8:30 AM to make a 10:00 AM class. He
starts treatment with light by walking to class to get
6. What intervention would be most helpful in a patient bright light exposure (~910 AM). Unfortunately, using
with ASPD? this regimen, he is unable to fall asleep any earlier. What
A. Evening light. do you recommend for initial treatment?
B. Morning light. A. Wear dark glasses on walk to 10 AM class, get bright
C. Evening melatonin. light exposure after 12 noon.
D. Morning melatonin. B. Wake up at 8 AM, light box for 1 hour, light exposure
on walk to 10 AM class.
7. What set of interventions would be most helpful for a
C. Wear dark glasses on walk to 10AM class, bright light
night shift worker (Table 2614)?
exposure after 3 PM.
8. A blind patient is found to have the non24-hour circa- D. Continue present light exposure, add melatonin 5
dian rhythm disorder. His desired bedtime is 11 PM. hours before habitual sleep time.
What treatment do you recommend?
A. Melatonin 5.0 mg at 8 AM. Answers
B. Melatonin 5.0 mg at 10 PM.
1. D. This patient has the DSPD. It is important to use
C. Melatonin 0.5 mg at 7 PM. bright light treatment after the CBTmin. The timing of
D. Melatonin 0.5 mg at 10 PM. the CBTmin is not known but can be estimated from the
spontaneous wake time. In normal subjects, the CBTmin
9. A businessman travels 5 hours eastward. What time
occurs about 2 hours before wake time. It may be some-
should light be avoided in the new time zone?
what earlier in patients with DSPD. With a normal wake
A. 6 AM9 AM. time of 11:00 AM, one could estimate a CBTmin around
B. 11 AM2 PM. 9 AM or slightly earlier. Of interest, the patient is exposed
C. 2 PM6 PM. to light on his way to work (67 AM). This may be on the
phase advanced side of his temperature minimum and
10. A patient with the DSPD has a habitual sleep time of 3 worsen the problem. He should wear dark glasses on the
AM and wake time of 11 AM on the weekends. When way to work in the morning.
should melatonin be administered?
A. 3 AM. 2. C. 24.2 hours.
B. 2 AM. 3. D. The maximum phase advance for bright light occurs
C. 12 midnight. about 34 hours after the CBTmin. C is at the CBTmin,
D. 9 PM. the transition between the phase delay and the phase
advance regions. Light at A and B would phase delay.
11. Which of the following is not true about DLMO? Light at E would have less phase advancing effect.
A. Occurs 23 hours before habitual bedtime. 4. B. The major photosensors are the retinal ganglion cells
B. Occurs 1 hour before habitual bedtime. containing melanopsin.
5. C. Mutation of hPer2 gene has been associated with
TABLE 2614
familial ASPD.
Interventions for Night Shift Worker
6. A. Evening light will cause phase delay. Morning mela-
A Bright light Dark glasses Nap before
start of shift drive home night shift tonin will also cause a phase delay, but the hypnotic
effects are undesirable for most patients.
B Bright light Dark glasses Nap before
end of shift drive home night shift 7. A. Bright light at the start of the shift, dark glasses on the
C Bright light Delay bedtime Nap before
way home, going to bed on arrival at home, and a nap
start of shift until 11 AM night shift before the shift are suggested interventions. Light at the
end of the shift, on the way home, or during the first hours
D Bright light Delay bedtime Nap before at home could phase advance. A phase delay so that
end of shift until 11 AM night shift
CBTmin is within the daytime sleep period is desirable.
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542 Chapter 26 Circadian Rhythm Sleep Disorders
8. D. Melatonin given 1 hour before the desired bedtime
is recommended. Although 5 mg may work, some
patients will fail to entrain on 5 mg but entrain on a
lower dose. However, the AASM practice parameters
did not recommend a specific time or dose.
9. A. If the baseline CBTmin is assumed to be 4 AM, this
corresponds to 9 AM in the new time zone. The patient
must phase advance for adaptation. Light for several
hours before the CBTmin induces the most significant
phase delay. Light exposure should be avoided before 9
AM and pursued from 11 AM to 2 PM to induce the
maximum phase advancing effect. Light from 6 to 9 AM
may cause phase delay. Light at 2 to 6 PM is so far away
from the CBTmin that it has minimal effect.
10. D. Melatonin should be administered 5 to 7 hours
before habitual sleep time.
11. B. DLMO occurs about 2 to 3 hours before habitual
sleep time.
12. A. The patients CBTmin is probably around 11 AM (2 hr
before typical wake time on weekends). Bright light
exposure before 11 AM causes an unwanted phase delay.
The best option is to minimize light exposure before 11
AM and then seek bright light exposure for 12 hours
after 12 noon (after CBTmin for phase advance). Bright
light exposure at 3 PM will be less effective than light
exposure closer to the CBTmin. Melatonin 5 hours
before the habitual bedtime may help, but the most
important intervention is use of the correct exposure to
light.
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Clinical Electroencephalography
and Nocturnal Epilepsy
Chapter Points
Nocturnal epilepsy can be difficult to differentiate from
parasomnias because some patients have seizures only
at night, scalp EEG findings may not be visible during
seizures, bizarre movements can occur during partial
seizures, consciousness can be maintained, and
minimal postictal confusion may be present in some
cases.
NFLE manifests as three syndromes: paroxysmal
arousals (mimics confusional arousals), nocturnal
paroxysmal dystonia (dystonic posturing), and episodic
wandering (mimics sleepwalking). The paroxysmal
arousals and nocturnal paroxysmal dystonia episodes
tend to be brief.
Factors favoring NFLE over a parasomnia include
multiple episodes per night, stereotypical
manifestations, onset out of stage N2 versus N3, and
certain behaviors (e.g., cycling, fencing, pelvic
thrusting) as well as immediate alertness after the
episode.
In roughly 50% of the cases of NFLE, there is no
abnormality in the scalp EEG during the seizure (other
than artifact due to body movement).
The partial seizures of TLE are typically complex
partial seizures (consciousness is impaired during
the seizure). The partial seizures of FLE may be either
complex or simple (no impairment of consciousness).
Seizures from the supplemental motor area may
occur with intact responsiveness and no postictal
confusion. Classic manifestations of seizures from
the supplementary motor area include fencing with
head turned away from the outstretched arm,
kicking, laughing, or pelvic thrusting. Unlike
psychogenic activity, there is an abrupt onset and
offset.
Video PSG is essential for evaluation of patients with
possible nocturnal epilepsy. A substantial number of
patients with NFLE will not have either ictal or
interictal EEG findings and the type of body
movements (seminology) can be very helpful in
arriving at a correct diagnosis. Using an extended EEG
Chapter 27
montage and visualization of waveforms in a
10-second window is recommended.
The focal seizures of FLE are more likely to occur at
night than during the day. The focal seizures of TLE are
more likely to occur during the day than during the
night. FLE events during the day are more likely to
generalize. TLE events during the night are more likely
to generalize compared with those occurring during
the day.
Because mastoid electrodes are fairly near the
temporal lobes, interictal activity associated with TLE
can often be easily seen in standard PSG montages.
For example, a left temporal spike may be visible in
derivations containing M1. The spike will be more
prominent in C4-M1 than in C3-M2 even though the
spike is on the left.
Changing to a 10-second window is essential to
accurately identify interictal activity because spikes
may be difficult to see in the 30-second window. It is
useful to examine paroxysmal changes in EEG tracings
in a 10-second window to avoid incorrectly assuming
that ictal activity is an artifact.
ELECTROENCEPHALOGRAPHIC MONITORING
The international 10-20 system1,2 for electrode placement for
electroencephalographic (EEG) monitoring is illustrated in
Figure 271. Each electrode is represented by a letter that
represents the underlying area or lobe of the brain (Fp =
frontopolar; F = frontal; P = parietal; O = occipital; T = tem-
poral) (Fig. 272) and numerical subscripts representing
position. The odd subscripts are on the left and the even on
the right, and the z subscripts refer to electrodes in the
midline.1,2 The left and right auricular (earlobe) electrodes
are A1 and A2. In sleep monitoring, these are actually placed
on the mastoids and termed M1 and M2.3 Figure 271 illus-
trates the new electrode nomenclature1 in which T7, T8, P7,
and P8 have replaced T3, T4, T5, and T6. In the new nomen-
clature, all electrodes in a given sagittal plane have the same
subscript (F7, T7, P7) and most electrodes in the same coronal
plane have the same letter (P7, P3, Pz, P4, P8). However, many
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546 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy

Fp1 Fp2 Fp1 Fp2

F7 F3 F4 F8 F7 F3 F4 F8
FZ FZ

A1 A2 A1 A2
T7 C3 CZ C4 T8 T3 C3 CZ C4 T4

P3 PZ P4 P3 PZ P4
P7 P8 T5 T6

O1 O2 O1 O2

New Old
FIGURE 271 Electrode nomenclature (new and old terminology). T3 and T4 are replaced by T7 and T8 and T5 and T6 are replaced by P7 and P8.

Supplementary Mesial
motor area Central Mesial frontal
fissure frontal lobe
Cz Su
p fr
ont
al g
Fz Cingulate gyrus yru
tex

s
cor

F3 Pz Corpus callosum
C3
tor

Fornix
Mo

Frontal lobe Parietal lobe P3 Hipp

ocam
pal g
Fp1 F7 Occipital lobe yrus
Temporal
Insula
T7 lobe
P7 Oz Mesial
Temporal lobe temporal lobe Basal and
mesial temporal

Sagittal section through midline Coronal section

FIGURE 272 Schematic views of the brain illustrate areas of interest for epilepsy and electroencephalography (EEG) monitoring. The central fissure is also known as the Rolandic
fissure.

Cz Cz
20%
20% Fz
Pz 20% C3 C4
C3 Fz Pz
F4 20% F4 F3
20% P4 P3 P4
20%
Fpz F8 Fp2 Fp1 F7
Fp1
Oz F8 10% P7 O1 O2 P8
O2 P8 T8
10% 10% Nasion
Inion Preauricular
A1
point

FIGURE 273 The 1020 system of electrode placement. All electrodes are placed either 10% or 20% of the distance between two standard landmarks.

EEG laboratories still use the old electrode nomenclature as BIPOLAR MONITORING AND
does the majority of the published literature on epilepsy. Of
STANDARD MONTAGES
note, the 10-20 electrode position2 refers to the fact that elec-
trodes are positioned at 10% or 20% of the distance between A derivation is the voltage difference between electrodes: for
landmarks such as nasion, inion, or the preauricular points example, Fp1-F3 is the voltage difference between electrodes
(Fig. 273). Fp1 and F3. By electroencephalography (EEG) convention, if
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 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 547

Fp1 is more negative than F3, the deflection is up.4,5 A set of electrodes with the ipsilateral auricular electrodes A1 and A2
derivations is called a montage. Montages are designed with (see Table 272). Different laboratories may display the elec-
a particular purpose in mind. Standard montages for sleep trodes in a given montage in different sequences. In modern
monitoring were illustrated in Chapter 1. Tables 271 and digital EEG recording, all electrodes are usually recorded
272 show standard clinical EEG montages.6 Bipolar longi- against a common reference. Then any two electrodes may
tudinal montages (Fig. 274; see also Table 271) sequen- be compared by digitally subtracting the signals (F7-ref)
tially compare two adjacent electrodes in chains covering the (P7-ref) = F7-P7. Thus, one can change the display montage
head in an anteroposterior (AP) direction (double banana). while recording or later during study review. Digital record-
In the most frequently used variant (LB-18.1), the chains ing also allows one to visualize multiple time scales. The
start at the left temporal area and then progressively move polysomnography (PSG) window to stage sleep is 30 seconds
toward the right. Bipolar transverse montages compare two but the clinical EEG window is 10 seconds. The 10-second
electrodes in chains in the transverse directions (Fig. 275; time window allows detection of brief, sharply contoured
see also Table 272). Referential montages compare waveforms that may signify seizure activity.

Longitudinal Biopolar

1 Fp1 Fp2 15 11 Fp1 Fp2 15 1 Fp1 Fp2 5

F7 5 11 F8 F7
3 7 F8 F7 9 13 F8
F3 Fz F4 F3 Fz F4 16 F3 Fz F4
2 16 12 6
2
6 9 12 4 1 8 10 17 14
T7 C3 Cz C4 T8 T7 C3 Cz C4 T8 T7 C3 Cz C4 T8

7 10 13 5 2 9 11 18 15
3 17 17 3 7
13
P3 Pz P4 P3 Pz P4 P3 Pz P4
P7 P8 P7 P8 P7 P8
8 14 6 10 12 16
4 O1 O2
18 14 O1 O2 18 4 O1 O2 8

LB-18.1 LB-18.2 LB-18.3

LB-18.1
FIGURE 274 Longitudinal bipolar montage chains. LB-18.1, LB-18.2, and LB-18.3 are three methods of arranging the derivations for display.

Transverse bipolar

2 1
1 Fp1 Fp2 3 Fp1 Fp2

F7 F8 F7 2 3 4 5 F8
4 F3 Fz F4 F3 Fz F4
5 6 7
17
A1 A2
T7 C3 Cz C4 T8 T7 C3 Cz C4 T8 11
8 9 10 11 6 7 8 9 10
18
12 13 14 15
P3 Pz P4 P3 Pz P4
P7 P8 P7 13 14 P8
12 15
16 O1 O2
18 O1 O2
17 16

TB-18.1 TB-18.2
FIGURE 275 Transverse bipolar montages.
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548 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy

TABLE 271
Longitudinal Bipolar (AP Bipolar) 18-Channel Double Banana
LB-18.1 LB-18.2 LB-18.3
Fp1-F7 Left temporal Fz-Cz Vertex Fp1-F7 Left temporal
F7-T7 Cz-Pz F7-T7
T7-P7 T7-P7
P7-O1 P7-O1
Fp1-F3 Left parasagittal Fp1-F3 Left parasagittal Fp2-F8 Right temporal
F3-C3 F3-C3 F8-T8
C3-P3 C3-P3 T8-P8
P3-O1 P3-O1 P8-O2
Fz-Cz Vertex Fp2-F4 Right parasagittal Fp1-F3 Left parasagittal
Cz-Pz F4-C4 F3-C3
C4-P4 C3-P3
P4-O2 P3-O1
Fp2-F4 Right parasagittal Fp1-F7 Left temporal Fp2-F4 Right parasagittal
F4-C4 F7-T7 F4-C4
C4-P4 T7-P7 C4-P4
P4-O2 P7-O1 P4-O2
Fp2-F8 Right temporal Fp2-F8 Right temporal Fz-Cz Vertex
F8-T8 F8-T8 Cz-Pz
T8-P8 T8-P8
P8-O2 P8-O2
From American Clinical Neurophysiology Society: Guideline 6: a proposal for standard montages to be used in clinical EEG. J Clin Neurophysiol 2006;23:111117.

If the capacity to add a few electrodes to traditional sleep
monitoring exists, one can increase the ability to detect epi-
leptiform activity. For example, one could add two electrodes
(T7, T8). The derivations F3-T7, T7-O1, F4-T8, and T8-O2 would
add coverage over much of the frontal and temporal areas.
These areas are the predominant foci of seizures occurring
mainly during sleep. Other clinicians have utilized the addi-
tion of Fz, Cz, F7, and F8 to the usual PSG electrodes.7 The
addition of synchronized digital video monitoring to noctur-
nal EEG or PSG recording greatly enhances the ability of the
clinician to diagnose nocturnal events.8 As is discussed later,
many nocturnal seizure disorders are not associated with
scalp EEG findings and the patients actions during the
seizure (seminology) may be very helpful in determining
whether an episode is likely a parasomnia or nocturnal
epilepsy.8
WAVEFORM AND SEIZURE TERMINOLOGY
The terminology and identification of epileptic seizures and
interictal activity is challenging for physicians without exten-
sive training in EEG (Table 273). A transient is any isolated
wave or complex that stands out compared with background
activity. A spike is defined as a transient with a pointed peak
and a duration of 20 to 70 msec (Fig. 276). On a 30-second
page, spikes look like a single vertical line. A sharp wave is
a transient with a deflection of 70 to 200 msec.
A spike and wave complex is a spike followed by a slow
wave (usually wide and often higher amplitude). Polyspike
complexes often consist of multiple spikes superimposed on
a slow wave. The term epileptiform activity literally means
EEG activity resembling that found in patients with epi-
lepsy. This is a somewhat circular definition. Interictal
activity is defined as abnormal EEG activity that occurs
between seizures. Epileptiform activity includes spikes, spike
and waves, and polyspike complexes. Abnormal sharp waves
are also considered epileptiform or interictal activity. Of
course, sharp waves can be normal (e.g., vertex sharp waves).
Artifacts can sometimes mimic spikes or spikes and waves.
In general, true spike and wave complexes have a field (Box
271). That is, true spike and wave activity should be seen
in derivations containing several contiguous electrodes.
If a spike and wave is seen only in a single derivation, the
activity is usually be an artifact.
Because seizures do not always appear during a given
recording (see Box 271), the physician reading an EEG or
PSG searches for spikes and/or abnormal sharp waves that
may represent the interictal footprint of possible seizure
activity. However, it should be noted that not all patients with
spikes have seizures and not all patients with seizures have
detectable interictal activity. Spikes represent abnormal
brain activity that is seen as an area of negativity at the scalp.
Spikes can be localized (negativity at the scalp over one area
of the brain) or appear diffusely. Focal seizures usually,
though not invariably, begin at the same location as the
interictal spikes. The classic spike is followed by a slow wave.
Although most common postictally, spike and sharp waves
will occur sporadically at any time and may have a slight
increase preictally. Using the usual 30-second time window,
it may be difficult to appreciate spikes. A switch to a 10-second
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 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 549

TABLE 272 BOX 271

Transverse Bipolar and Referential Montages Useful Facts about Electroencephalography
(18 Channels) and Epilepsy
TRANSVERSE BIPOLAR REFERENTIAL
INTERICTAL EEG
TB-18.1 TB-18.2 R-18.1 R-18.2 R-18.3 A true spike and wave is rarely confined to one
F7-Fp1 Fp1-Fp2 F7-A1 Fz-A1 F7-A1 derivationi.e., has a field of involvement (especially
true if a typical bipolar clinical EEG montage is used).
Fp1-Fp2 T7-A1 Pz-A2 F8-A2
A spike confined to one derivation is often an artifact.
Fp2-F8 F7-F3 P7-A1 T7-A1 ECG artifact can mimic spikes.
F3-Fz Fp1-A1 T8-A2 ICTAL EEG
F7-F3 Fz-F4 Fp1-A1 Fp2-A2 P7-A1 Typically, ictal EEG activity evolves in
Frequencymay increase then exhibit postictal slowing.
F3-Fz F4-F8 F3-A1 F3-A1 P8-A2
Fieldamount of involved derivations increases.
Fz-F4 C3-A1 F4-A2 Amplitudemay increase.
F4-F8 A1-T7 P3-A1 C3-A1 Fp1-A1 Background rhythms are often suppressed.
T7-C3 O1-A1 C4-A2 Fp2-A2 EEG AND EPILEPSY

T7-C3 C3-Cz P3-A1 F3-A1 A single EEG will show epileptiform abnormalities in
about 50% of adult patients with epilepsy.
C3-Cz Cz-C4 Fz-A1 P4-A2 F4-A2
Diagnostic yield increased to 70% with repeated
Cz-C4 C4-T8 Pz-A1 O1-A1 C3-A1 recordings and/or sleep EEGs.
A normal EEG does NOT rule out epilepsy.
C4-T8 T8-A2 O2-A2 C4-A2
An abnormal EEG (epileptiform activity) does NOT rule in
Fp2-A2 P3-A1 epilepsy.
P7-P3 P7-P3 F4-A2 F7-A1 P4-A2 ECG = electrocardiogram; EEG = electroencephalography.

P3-Pz P3-Pz C4-A2 F8-A2 O1-A1

Pz-P4 Pz-P4 P4-A2 T7-A1 O2-A2 window is indicated to scrutinize any suspicious paroxysmal
P4-P8 P4-P8 O2-A2 T8-A2 activity.
P7-A1 Fz-A1
P7-O1 O1-O2 F8-A2 P8-A2 Pz-A2 PHASE REVERSAL
O1-O2 Fz-Cz T8-A2 Localized EEG waveforms (including spikes and sharp
waves) will show phase reversal if the bipolar chain crosses
O2-P8 Cz-Pz P8-A2
the area of the localized EEG activity.4,5 Phase reversal does
From American Clinical Neurophysiology Society: Guideline 6: a proposal for
standard montages to be used in clinical EEG. J Clin Neurophysiol
not imply an abnormal waveform. For example, K com-
2006;23:111117. plexes and vertex sharp waves show phase reversal in mon-
tages that cross the location of origin. Phase reversal may
help differentiate epileptiform activity such as a spike from
artifact. Epileptiform activity is recorded as an electronega-
tive potential. For example, in Figure 277A, negative spike
TABLE 273
activity is seen under electrode T7. This results in down-
Waveform Terminology
going deflections in F7-T7 because T7 is more negative than
Spike Transient with a pointed peak and F7. This pattern reverses for T7-P7 because now P7 is more
duration of 2070 msec positive than T7. In this figure, s is for spike and w is for
Polyspike Transient with multiple spikes wave. If the spike focus is located nearly equidistant between
two monitoring electrodes (F8 and T8) (see Fig. 277B), the
Sharp wave Transient with a pointed peak and
derivation containing them may show little or no activity
duration of 70200 msec
(F8-T8) and the derivations on either side will show phase
Interictal discharge Abnormal (epileptiform) EEG activity reversal ([Fp2-F8] to [T8-P8]).
that occurs between seizures
Spike and wave Spike followed by a slow wave LOCALIZATION IN REFERENTIAL
AND PSG MONTAGES
Ictal activity EEG correlate of a seizure
In referential montages, a spike will have greater activity in
EEG = electroencephalogram.
montages containing electrodes nearer to the location of the
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550 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy

FIGURE 276 Sharp waves, spikes, spike and wave, polyspikes, 10 sec page 30 sec page
and polyspike and wave. EEG = electroencephalography; PSG = (30 mm/sec) (10 mm/sec)
polysomnography. EEG speed PSG speed

Sharp waves

Spikes

Spike and wave

1 second
Polyspikes

Polyspike
and wave
1 second

Nasion Nasion
Seizure
Seizure focus
Fp1 Fp2 Fp1 - F7 Fp1 Fp2 Fp2 - F8
focus
F7 F3 Fz F4 F8 F7 F3 Fz F4 F8
F7 - T7 F8 - T8
Left T7 C3 Cz C4 T8 Right Left T7 C3 Cz C4 T8 Right

P7 P3 P8 T7 - P 7 P7 P3 P8 T8 - P 8
Pz P4 S Pz P4
W
O1 O2 P7 - O1 O1 O2 P8 - O2

A Inion B Inion

FIGURE 277 Examples of phase reversal. A, A spike (s; negative) originates at electrode position T7 and a bipolar chain through the area shows phase reversal.
w = wave. B, Spike originated in between electrodes. The bipolar pair spanning the location show low amplitude due to cancellation effects but bipolar pairs on either
side show phase reversal.

FIGURE 278 Difference in localization with a bipolar or a Nasion

referential montage. In referential montages, the electrode(s)
nearest the activity in question has the largest deflection. Spike focus
Fp1 Fp2 Fp2 - F8 Fp2 - Ref

F7 F3 Fz F4 F8
F8 - T8 F8 - Ref
Left T7 C3 Cz C4 T8 Right
T8 - P8 T8 - Ref
P7 P3 Pz P4 P8

O1 O2 P8 - O2 P8 - Ref

Inion

spike. In Figure 278, a spike focus is located between F8 and
T8. On the bipolar montage, this results in the electrical
activity being nearly equal in the two electrodes, resulting in
minimal activity in F8-T8 but a phase reversal in adjacent
bipolar pairs. However, in referential recording, the spike
results in larger and nearly equal activity in F8 and T8 with
less activity in adjacent electrodes. In the usual PSG montage,
electrodes are referenced to the opposite mastoid.3 Therefore,
a spike located near F4 will result in greater deflection in F4-
M1 compared with C4-M1 or O2-M1. It is also important to
recall that the mastoid electrodes may actually be closer to
spikes in the temporal area than the F4, C4, and O2 electrodes.
For example, a left temporal focus of activity may be nearer
M1 than F3, C3, and O1. Thus, C4-M1 will actually show more
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 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 551

activity from a left temporal focus than C3-M2 because M1 is

closer to the temporal area than C3. In the case of a left tem-
poral spike, one would expect to see epileptiform activity in
most channels referenced to the left mastoid (M1).
NORMAL SLEEP WAVEFORMS
IN THE 10-SECOND WINDOW
The standard waveforms and eye movements used to stage
sleep have a different appearance when viewed in a 10-second
window in a standard clinical EEG montage. With digital
PSG, one can change the time base (10-second to 30-second
window) and vice versa to help with waveform recognition.
Eye Movements and Bells Phenomenon
Bells phenomenon describes the reflex upward movement of
the front of the eyeball when the eyelids close (or blink).
Because the cornea is positive with respect to the retina, this
causes a deflection in derivations containing electrodes
placed near the eyes (Fp1, Fp2). Recall that if G1 becomes posi-
tive with respect to G2, the derivation G1-G2 shows a down-
ward deflection. Thus, eyelid closure results in downward
deflections in Fp1-F7 and Fp2-F8. This is illustrated in Figures
279 to 2711.
Conjugate vertical eye movements result in characteristic
deflections in bipolar derivations. The deflections depend on
which electrodes are closer to the eyes. For vertical move-
ments, the Fp1 and Fp2 electrodes are more positive (eyes up)
or negative (eyes down) compared with adjacent electrodes
(see Fig. 2710). For lateral eye movements, the electrodes
F7 and F8 become more positive or negative than adjacent
electrodes (see Fig. 2711). Thus, in longitudinal bipolar
derivations, vertical eye movements cause in-phase deflec-
tions and lateral movements result in out-of-phase
deflections.
Posterior Rhythm
The term alpha rhythm is used to denote waveforms of 8 to
13 Hz that are prominent in occipital derivations and decrease
in amplitude with eye opening. However, the preferred term
is posterior rhythm or dominant posterior rhythm (DPR).
The DPR of infants and children is discussed in Chapter 5.
The DPR frequency is slower than 8 Hz in infants and young
children. The average frequency of the DPR increases to
approximately 8 Hz at 8 years of age in the majority of indi-
viduals (8 Hz by 8 years is OK). With eyes closed and/or
decreased visual attention, the DPR becomes prominent.
With drowsiness and transition to stage N1, the occipital
derivations show attenuation of the DPR and replacement
with theta activity. The effect of eyes open and eyes closed on
the DPR in an adult is illustrated in Figure 2712. As noted
previously, eyes closed results in an upward deflection of the
eyes (under the eyelids) and a characteristic downward
deflection in derivations near the eyes (see Fig. 2712).
Some familiar waveforms used to stage sleep are displayed
in a bipolar montage using a 10-second window in Figure
2713. Stage R is shown in Figure 2714. Note the rapid eye
EYELID CLOSURE EYELID OPENING
Fp1 Fp1 Fp1
F7 F7 F7


Fp1 - F7
FIGURE 279 Bells phenomenon. With eyelid closure (and blinks), the globe turns
upward. This results in characteristic deflections in derivations containing electrodes
near the eyes. The cornea is positive with respect to the retina.

Vertical eye movements Fp1 and Fp2 are more

positive or negative than adjacent electrodes

Up
Fp2 Fp1 Fp1 - F7
F8 F7 F7 - T7
Cornea   retina
Fp1 compared to F7 Fp2 - F8
F7 compared to T7 F8 - T8
F3
Fp2 compared to F8
Fp1 T7
F8 compared to T8
F7

Down
Fp2 Fp1 Fp1 - F7
F8 F7 F7 - T7

Fp1 compared to F7 Fp2 - F8

F7 compared to T7 F8 - T8
Fp2 compared to F8
F8 compared to T8

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FIGURE 2710 Effect of vertical eye movements on bipolar derivations containing electrodes near the eyes.
552 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy

Lateral eye movements F7 and F8 are

more positive or negative than adjacent electrodes

Right
Fp2 Fp1 Fp1 - F7
F8 F7
F7 - T7
Cornea   retina
Fp1 compared to F7 Fp2 - F8
F7 compared to T7 F8 - T8
F3
T7 Fp2 compared to F8
Fp1
F7 F8 compared to T8

Left
Fp2 Fp1 Fp1-F7
F8 F7 F7 F7-T7
Fp2-F8
Fp1 compared to F7
F7 compared to T7 F8-T8
Fp2 compared to F8
F8 compared to T8

FIGURE 2711 Effect of lateral eye movements on bipolar derivations containing electrodes near the eyes.

Fp1-F7 Fp1-F7
F7-T7 F7-T7
T7-P7 T7-P7
P7-O1 P7-O1
Fp2-F8 Fp2-F8
F8-T8 F8-T8
T8-P8 T8-P8
P8-O2 P8-O2
Fp1-F3 Fp1-F3
F3-C3 F3-C3
C3-P3 C3-P3
P3-O1 P3-O1
Fp2-F4 Fp2-F4
F4-C4 F4-C4
C4-P4 C4-P4
P4-O2 P4-O2
Fz-Cz Fz-Cz
Cz-Pz Cz-Pz
ECG ECG

Eyes closed 1 sec Eyes open

FIGURE 2712 Effect of eye closure and opening on the alpha rhythm (dominant posterior rhythm). The rhythm is increased with eye closure or visual inattention and attenuated
by eye opening and most prominent in derivations containing O1 and O2. Recall that with eye closure, the eyes turn upward under the eyelids (Bells phenomenon). ECG =
electrocardiogram.

movements appear much wider in the 10-second window
than in a 30-second time window.
Positive Occipital Sharp Transients of
Sleep and Lambda and Mu Rhythms
Positive occipital sharp transients of sleep (POSTS) are
sharp waves that can occur normally in nonrapid eye move-
ment (NREM) sleep. They are most prominent in occipital
derivations and are positive. Therefore, in O1-M2, they would
be downward deflections (O1 is positive compared with M2).
In Figure 2715, the POSTS show phase reversal across O1.
The fact that the POSTS are in fact positive in the occipital
area is documented by the fact that the deflections are up in
C3-O1 and downward in O1-M1.
Lambda waves have similar morphology and location as
POSTS but lambda waves are noted during wakefulness.
Lambda waves are low-voltage triangular waves that appear
in the occipital areas. They may be surface positive or nega-
tive (POSTS are surface positive) (Fig. 2716).
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 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 553

50 V
1 sec

Fp1-F7 Fp1-F3
F7-T7 F3-C3
T7-P7 C3-P3
P7-O1 P3-O1

Fp1-F3 Fp2-F4
F3-C3 F4-C4
C3-P3 C4-P4
P3-O1 P4-O2

Fz-Cz Fp1-F7
Cz-Pz F7-T7
V V SS T7-P7
Fp2-F4 P7-O1
F4-C4 K
C4-P4 Fp1-F8
P4-O2 F8-T8
T8-P8
Fp2-F8 P8-O2

F8-T8
T8-P8 T7-C3
P8-O2 C3-CZ
sec CZ-C4 P
C4-T8

A B C

FIGURE 2713 Waveforms of sleep using a clinical EEG montage (longitudinal bipolar) and a 10-second window. Vertex sharp waves (V; A), sleep spindles (SS; B), and a K
complex (K; C) are shown. Note phase reversal across Cz in the vertex sharp waves (A) and for K complex in C as denoted by P.

F3-C3
C3-O1
F4-C4
C4-O2
F3-T3
T3-O1
F4-T4
T4-O2
F3-F4
M1-T3
T3-C3
C3-C4
C4-T4
T4-M2
O1-O2

E1-M2
E2-M2
Chin
100 V 1 sec

FIGURE 2714 Stage R using a clinical EEG montage (combination of longitudinal and transverse bipolar) and a 10-second window. The underlined activity is a saw-tooth wave
(theta activity prominent in central derivations). Note also that alpha activity is common during stage R and usually 12 Hz slower. Alpha activity is seen in the occipital derivations
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at the same time as the saw-tooth waves. However, note that the alpha bursts stop before the saw-tooth activity ends. Note older electrode terminology (T3, T4 instead of T7, T8).
554 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy

100 V

F4-M1 F4-M1
C4-M1 C4-M1
O2-M1 O2-M1
E1-M2 E1-M2
E2-M2 E2-M2
Chin Chin
A B

C3-O1
O1-M1

FIGURE 2715 Positive occipital sharp transients of sleep (POSTS) as seen in typical PSG montage in a 30-second (A) and a 10-second window (B). C, Bipolar derivations containing
the occipital electrode show that there is a phase reversal at O1 and that the waves are positive (downward deflection in O1-M1). The vertical lines are 1 second apart.

1 sec

lambda

Fp1-F3
F3-C3
C3-P3
P3-O1

Fz-Cz
Cz-Pz

FIGURE 2716 Lambda waves are noted in the P3-O1 derivation and marked by dots under the waves. Adapted from Libenson MH: Practical Approach to Electroencephalography.
Philadelphia: Elsevier Saunders, 2010, p. 270.

Mu rhythm may sometimes be confused with alpha TABLE 274

rhythm but differs in a number of features, listed in Table Mu Rhythm
274. Mu rhythm is seen in central derivations during wake MU ALPHA
and has an archiform or comblike shape with rounded
contour on one side and sharp contour on the other (Fig. Stage Wake Drowsy wake
2717). Mu rhythm is most prominent in central areas Frequency (Hz) 813 813
(rather than occipital) and is reactive to movement of the
Location Central (C3, C4) Occipital
contralateral hand (rather than opening of the eyes).
Reactivity, diminished Movement of Opening eyes
ICTAL ACTIVITY with contralateral hand

Ictal (seizure) activity may be manifested by rhythmic activ- Shape Archiform Sinusoidal
ity of many types. By definition, to be considered ictal, a Comblike
given burst of activity must be associated with an abnormal-
ity of movement or mentation. Whereas the spike and wave
activity is the most familiar waveform associated with ictal activity. In Figure 2719, a portion of a tracing visualized in
activity (Fig. 2718), the pattern of repetitive sharp waves of a 10-second window shows a spike and wave complex (SW)
various frequencies is also common.4,5 On traditional sleep followed by rhythmic activity of 8 to 9 Hz (R). The rhythmic
monitoring montages, ictal activity can even be mistaken for activity is differentiated from normal alpha rhythm by being
muscle artifact or normal alpha (813 Hz) and beta (>13 Hz) more prominent in the eye derivations than in the occipital
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 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 555

Cz-Pz

Fp2-F4

F4-C4

C4-P4

P4-O2

FIGURE 2717 An example of mu rhythm (archiform comb like pattern with phase reversal at C4). The vertical lines are 1 second apart. From Libenson MH:
Practical Approach to Electroencephalography. Philadelphia: Elsevier Saunders, 2010, p. 272.

FIGURE 2718 A seizure beginning as focal activity

in the right frontal-temporal areas with secondary
generalization.
Fp1-F7

F7-T

T-P7

P7-O1

Fp2-F8

F8-T8

T8-P8

P8-O2

1 sec

FIGURE 2719 A spike and wave (SW) complex is

followed by rhythmic activity (R) in the alpha frequency
F3-M2 range that represents ictal activity in a patient with
frontal lobe seizure. The origin is the right frontopolar
C3-M2
area and the largest amplitude is seen in E2-M2 and
O1-M2 F4-M1.

F4-M1

C4-M1

O2-M1

E1-M2
R
E2-M2

sw
1 sec
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556 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy
derivations. This is, in fact, a portion of a frontal seizure
manifested by oral automatisms and loss of responsiveness.
One might suspect the frontal nature because the activity is
higher amplitude in the eye leads (near the frontal lobes). A
complete EEG montage documented a right frontal location
(note in Fig. 2719, slightly higher amplitude in E2-M1 than
in E1-M2).
As previously mentioned, ictal activity may not be seen
in scalp EEG monitoring. Video recording is absolutely
essential because the pattern of movements (seminology) is
very important for helping differentiate nonepileptic move-
ments (parasomnias) from epileptic movements. The type of
movement and the focal or generalized distribution may
help define the type of seizure and/or focus in partial or
partial complex seizures. High-resolution magnetic reso-
nance imaging (MRI) or invasive EEG monitoring may also
identify the epileptic location in the brain.
Ictal activity can be mistaken for a recording artifact and
vice versa. Some useful characteristics of true ictal activity
are noted in Box 271. True ictal activity evolves (i.e., changes
in frequency, amplitude, and distribution) during the
episode. There is often EEG slowing after an ictal episode.
Synchronized video is very useful to determine whether
there are behavioral correlates (e.g., movements) temporally
associated with ictal activity.
CLASSIFICATION OF SEIZURES
AND TERMINOLOGY
A seizure is defined as an episode of disturbance of mental,
motor, sensory, or autonomic activity caused by a paroxys-
mal cerebral neuronal malfunction. Epilepsy is defined as a
disorder of recurrent seizures. The disorder is called symp-
tomatic if there is an identifiable lesion or idiopathic if a
discrete structural abnormality is not found. The term idio-
pathic is misleading because many seizure disorders classi-
fied as idiopathic have a genetic basis and some have a
known mechanism.
The most commonly used classification of seizures is
based on their manifestations9 (Box 272). Seizure disorders
are divided into partial (focal) seizures that are due to the
initial involvement of a localized group of neurons limited
to one hemisphere. If consciousness is not impaired, the
disorder is termed a simple partial seizure (SPS). If con-
sciousness is impaired, the disorder is a complex partial
seizure (CPS). An aura is an SPS manifested by sensations
preceding a seizure and is, in fact, a manifestation of focal
epilepsy. Automatisms are repetitive movements that may
be purposeful but serve no obvious purpose in the actual
situation. The postictal state is the state following ictal
activity often associated with impaired sensorium or confu-
sion. Simple partial seizures may not show an EEG abnor-
mality with scalp EEG recording. Complex partial seizures
usually do exhibit some abnormality. Partial seizures may
show secondary generalization (see Fig. 2718), resulting
in the ictal activity associated with generalized convulsive
seizures.
In Box 272, the partial epilepsies are divided into simple
partial (consciousness not impaired), complex partial (con-
sciousness impaired), and focal seizures (simple or partial
complex) that evolve into generalized seizures. The simple
partial seizures are divided into those with (1) motor symp-
toms, (2) somatosensory symptoms, (3) autonomic symp-
toms, and (4) psychic symptoms or signs. The complex
partial seizures are divided based on whether or not impaired
consciousness is apparent at the start of the seizure.
Primary generalized seizures are ones in which initial
manifestations involve both hemispheres usually with loss of
consciousness (or impairment), bilateral motor activity, or
both. As noted previously, generalized epilepsy is associated
with a diffuse origin of the seizure activity and is always
associated with impairment (usually loss of consciousness).
Generalized epilepsy is divided into nonconvulsive (absence
or petit mal) epilepsy and convulsive.
Nonconvulsive epilepsy is divided into typical (3/sec
spike and wave activity) and atypical with slower frequency
complexes. Nonconvulsive generalized epilepsy starts in
childhood and may resolve by late adolescence to adulthood.
Typical absence (petit mal) epilepsy (AE) is associated with
impairment of consciousness (staring blankly) without loss
of muscle tone or posture. Attacks are triggered by hyper-
ventilation and photic stimuli. Atypical AE is associated with
spike and wave complexes of less than 3/sec frequency and
may be associated with combinations of impaired conscious-
ness and motor or autonomic changes. Patients with atypical
nonconvulsive epilepsy may develop convulsive generalized
seizures later in life.
Convulsive generalized epilepsy is divided into myo-
clonic, tonic, clonic, tonic-clonic, and atonic seizures.
Myoclonic seizures are characterized by brief muscle jerking
(muscle contraction then relaxationoften involving the
shoulder muscles). An example of this type is juvenile myo-
clonic epilepsy (JME). Tonic seizures are associated with
muscle tensing. Clonic seizures manifest with repeated
jerking (repeated contraction and relaxation). Generalized
tonic-clonic (GTC) seizures (grand mal) are characterized
by initial tonic activity followed by clonic activity. Atonic
seizures are characterized by a sudden loss of muscle tone
(drop attacks).
Unclassified seizures are ones in which the origin (focal
or general) has not been determined.
Nocturnal Epilepsy
Seizure disorders are part of the differential diagnosis of
nocturnal spellsparticularly episodes of abnormal motor
activity occurring during sleep or soon after awakening.
Depending on the type of patients studied, as many as 10%
to 40% of seizures occur exclusively or mainly during
sleep. The lack of daytime seizure activity and the fact that
automatisms or episodes of changed sensorium during sleep
may not be noted by a bed partner or remembered by the
patient make simple partial or partial complex seizures dif-
ficult to diagnose. Some seizures such as those associated
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 Chapter 27
BOX 272
Classification of Seizures
1. PARTIAL (FOCAL, LOCAL) SEIZURES
A. Simple partial seizuzres (consciousness not impaired)
i. Motor symptoms
a. Focal motor without marchsustained tonic,
intermittent clonic, or a sequence of tonic-clonic
movements.
b. Focal motor with march (Jacksonian)move-
ments progressively involve adjacent parts of one
side of the body.
c. Versiveturning of head or body, usually in a dire-
tion away from the side of the seizure discharge.
d. Posturalinvoluntary changes in body posture.
e. Aphasicexpressive or receptive, global loss of
language.
f. Phonatory (vocalization or arrest of speech).
ii. Somatosensory or special sensory symptoms
a. Somatosensory.
b. Visualhallucinations.
c. Auditoryhallucinations of simple or complex
sounds.
d. Olfactoryhallucination of odors, often precedes
complex partial seizures.
e. Gustatoryhallucination of taste.
f. Vertiginoustransient vertigo.
iii. Autonomic symptoms or signs: epigastric, pallor,
sweating
iv. Psychic symptoms or signs (usually occur with
impairment of consciousness and classified as
complex partial)
a. Dysphasic.
b. Cognitive.
EEG = encephalogram.
Adapted from Commission on Classification and Terminology of the International League Against Epilepsy: Proposal for revised classification of epilepsies and
epileptic syndromes. Epilepsia 1981;22:389399.
with nocturnal frontal lobe epilepsy (NFLE) can occur
without loss of consciousness or postictal confusion and
may be incorrectly assumed to be a parasomnia. The inci-
dence of nocturnal seizures has two peaksone about 2
hours after bedtime and another between 4 and 5 AM (Table
275).10,11 Daytime seizures are most prevalent in the first
hour after awakening. In general, all manifestations of noc-
turnal seizure disorders are much more common in NREM
and rare during rapid eye movement (REM) sleep. Prior
sleep deprivation activates seizures; therefore, patients often
undergo clinical EEG monitoring in a sleep-deprived state
to increase the likelihood of recording seizure activity. Epi-
lepsy syndromes commonly associated with nocturnal sei-
zures are listed in Table 276.
Focal Nocturnal Epilepsy
General Characteristics
Focal seizure disorders are often associated with interictal
discharges or seizure activity in NREM sleep. The major
Clinical Electroencephalography and Nocturnal Epilepsy 557
c. Dysamnesic (dj vu).
d. Affective (fear).
e. Illusions.
f. Hallucinations.
B. Complex partial (with impairment of consciousness)
i. Simple partial onset followed by impairment of
consciousness
ii. Impairment of consciouness at onset
a. Impairment of consciousness only.
b. Automatisms.
C. Partial seizures (simple or complex) evolving to
generalized seizures.
2. GENERALIZED SEIZURES
A. Nonconvulsive (absence)petit mal
i. Typical (3/sec spike and slow wave on EEG)
ii. Atypical (<3/sec spike and slow wave complexes
on EEG)
B. Convulsive
i. Myoclonic seizuresbrief jerks
ii. Clonic seizures
iii. Tonic seizurestensing of muscles
iv. Tonic-clonic seizures (grand mal)
v. Atonic (drop attacks)
3. UNCLASSIFIED SEIZURE
types of focal nocturnal epilepsy are frontal lobe epilepsy
(FLE) and temporal lobe epilepsy (TLE). Herman and
coworkers12 studied patients with partial epilepsy undergo-
ing long-term video-EEG monitoring and found that FLE
seizures were significantly more common during sleep than
wake.10,11 In contrast, TLE seizures were more common
during wake. Figure 2720 illustrates the percentage of
each seizure type that occurs during wake and sleep. Some
patients with FLE have seizures only during sleep. TLE
is less likely to occur during sleep than during wake.
However, because TLE is much more common than FLE,
TLE is the most common type of nocturnal seizure. TLE
seizures at night are more likely to generalize than TLE
seizures during the day. In contrast, FLE seizures during
the day are more likely to generalize than those during
the night.
Nocturnal simple partial seizures result in focal motor,
sensory, autonomic, or psychic manifestations without a
change of consciousness. Complex partial seizures usually
arise from the mesial or lateral part of the temporal lobe or
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558 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy

TABLE 275 TABLE 276

Timing of Nocturnal Seizures and Effect of Sleep Epilepsy Syndromes Associated with Sleep
Interictal discharges NREM > wake > REM EPILEPSY SYNDROME TIME OF ONSET
Most frequent timing for About 2 hours after bedtime PARTIAL EPILEPSY
nocturnal seizures Between 4 and 5 AM
TLE Late childhood to early
Most frequent time for Within 1 hour of awakening adulthood
daytime seizures
FLE (including autosomal dominant Late childhood to early
Effect of sleep on seizures Incidence of seizures FLE) adulthood
NREM > wake > REM sleep
Secondary generalized partial Late childhood to early
Factors increasing seizures Sleep deprivation epilepsy adulthood
Medications lowering GENERALIZED EPILEPSY
seizure threshold
Benign centrotemporal epilepsy 313 yr (peak 910 yr)
PARTIAL EPILEPSY
with centrotemporal spikes
Interictal activity NREMcommon
Epilepsy with GTCS on awakening 625 yr (peak 1115 yr)
REMuncommon
JME 1218 yr (peak 14 yr)
Ictal activity NREMcommon
REMuncommon Absence epilepsy 312 yr (peak 67 yr)
GENERALIZED EPILEPSY Lennox-Gastaut syndrome 18 yr (peak 35 yr)
Interictal activity NREMcommon Continuous spike and slow wave 8 mo11.5 yr
REMrare discharges during sleep
FLE = frontal lobe epilepsy; GTCS = generalized tonic-clonic seizure;
Ictal activity NREMless common
JME = juvenile myoclonic epilepsy; TLE = temporal lobe epilepsy.
REMuncommon Adapted from Malow BA: Sleep and epilepsy. Neurol Clin 2005;23:1127.
After awakeningcommon
NREM = nonrapid eye movement; REM = rapid eye movement.

90 Awake Asleep 70 Awake Asleep

80
60
% seizures generalizing

70
50
60
% seizures

50 40
40 30
30
20
20
10 10

0 0
FLE TLE (all) MTLE NTLE OLE FLE TLE (all) MTLE NTLE OLE

FLE  frontal lobe epilespy NTLE  neocortical temporal lobe epilepsy

TLE  temporal lobe epilepsy OLE  occipital or parietal lobe epilepsy
MTLE  mesial temporal lobe epilepsy

FIGURE 2720 Left, The percentage of different seizure types occurring while awake and asleep. Note that frontal lobe epilepsy (FLE) occurs more
often during sleep than awake. Some patients with FLE may have seizures only at night. Temporal lobe epilepsy (TLE) is more likely to occur during awake
than sleep. Right, The percentage of focal epilepsy that generalized during awake and asleep. TLE occurring during sleep is more likely to generalize. FLE
occurring during awake is more likely to generalize. From Herman ST, Walczak TS, Bazil CW: Distribution of partial seizures during the sleep-wake cycle:
differences by seizure onset site. Neurology 2001;56:1456.

adjacent parts of the frontal lobe. The symptoms consist of
changes in the content of consciousness that reduce the
patients ability to interact with the surroundings. They can
occur with only a change in consciousness or can include
automatisms. For example, lip smacking is a common
automatism. Patients with complex partial seizures may have
no recollection of the events or only partial memory of the
seizure. Patients may remember an aura, a subjective
sensation such as a visual or olfactory disturbance that pre-
cedes the start of the event.
There have been efforts to identify characteristics allow-
ing differentiation between FLE and TLE. Unfortunately,
there is considerable overlap. FLE is more likely to be associ-
ated with dystonic posturing (fencing) and TLE more likely
to be associated with interictal or ictal activity visualized on
the scalp EEG.
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 Chapter 27
TEMPORAL LOBE EPILEPSY
TLE seizures begin focally and usually impair consciousness
(complex partial seizures). TLE seizures are more common
in NREM sleep but also occur at the transition from NREM
to REM sleep. Interictal activity can often be seen even using
traditional PSG EEG monitoring because the mastoid elec-
trodes are near the temporal lobes. Very rarely, no abnormal
EEG activity may be observed during seizures in some
patients with TLE using a full EEG montage of scalp elec-
trodes. TLE seizures may be manifested by lip smacking,
staring, episodes of an altered state of consciousness, con-
fused awakenings, and automatic behavior such as sleep-
walking or wandering through the house. Of note, partial
seizures with complex automatisms including vocalization
and violent behavior have been described in a few patients.
TLE can present with seizures that occur only at night.
Although FLE seizures are more commonly confined to sleep
than TLE seizures, because TLE seizures are much more
common, the most common partial seizure disorder occur-
ring only during sleep is TLE. However, as noted previously,
for most patients with TLE, seizures are more likely to occur
during the day than at night.
Mesial TLE
In adults, hippocampal sclerosis is the most common cause
of mesial TLE, whereas in children, cortical dysplasias and
low-grade malignancy are most common. Typical mesial
TLE consists of complex partial seizures with automatisms.
They start as simple partial seizures with sensory symptoms
(aura). Typical auras of mesial TLE include epigastric
(abdominal) and psychic auras (dj vu, jamais vu), and
fear). Dj vu (already seen) is the experience of already
experiencing something. Jamais vu (never seen) is the
experience of being unfamiliar with a person or situation
that is actually very familiar. The motor manifestations
include fine distal automatisms of finger, hands, or orobuccal
movements. Interictal EEG shows temporal sharp waves
maximal at anterior temporal electrodes. The ictal EEG is
often a well-defined theta (57 Hz) rhythmic pattern from
the temporal region (derivations containing T7, M1, T8, or M2
depending on the side of the body affected). High-resolution
MRI enhances the diagnosis demonstrating atrophy of the
hippocampus within the mesial temporal lobe.
Neocortical TLE
Seizures can be simple partial or complex partial depending
on the areas of the temporal lobe affected. Interictal EEG
shows spikes or sharp waves outside of the anterior temporal
area. Ictal EEG can show regional or widespread discharges.
PSG and TLE
The appearance of an interictal spike activity from the tempo-
ral lobe in the typical sleep montage can be misleading. The
Clinical Electroencephalography and Nocturnal Epilepsy 559
mastoid electrodes are located fairly close to the temporal
lobes. Therefore, derivations containing the mastoid elec-
trode on the same side as the temporal lobe may show promi-
nent activity even if the other part of the derivation is on the
other side of the brain. For example, C4-M1 might show
prominent activity from a left temporal focus despite the fact
that C4 is central in location and on the other side of the brain.
Prominent spikes in derivations containing M1 (near the left
temporal lobe) are shown in Figure 2721. The deflections are
downward because M1 is the second electrode in the deriva-
tion. Spikes are surface negative and here M1 is negative with
respect to F4, C4, and O2, resulting in downward deflections.
Ictal activity is shown from the same patient (Fig. 2722)
and consists of repetitive sharp waves most prominent on
the left and showing a phase reversal at T7 localizing the
seizure to the left temporal area. At the normal 30-second
window, the ictal activity could be mistaken for artifact.
NOCTURNAL FRONTAL LOBE EPILEPSY
NFLE is associated with a wide spectrum of manifestations
and is the type of epilepsy most likely mistaken as an NREM
or REM parasomnia.1014 In roughly half of the cases of
NFLE, there is no abnormality in the scalp EEG during the
episodes and many cases also have no interictal epileptiform
activity. In some of the cases with a normal scalp EEG,
abnormalities can be demonstrated by invasive EEG moni-
toring. The NFLE episodes are confined to sleep in most
cases, so they are less well observed. Patients often remain
conscious with minimal postictal confusion. Nocturnal
ambulation such as walking and crying and autonomic acti-
vation can mimic sleepwalking and sleep terrors. NFLE
exists in familial, sporadic, symptomatic (associated with
identifiable structural lesion), and idiopathic forms.
Of focal seizure disorders, approximately 20% have an
onset from the frontal lobes. The clinical manifestations of
frontal lobe seizures may vary depending on localization of
the epileptic focus. Seizures originating from the orbitofron-
tal areas and the cingulate gyrus (see Fig. 272) often
resemble those originating from the temporal lobes with
staring, nonresponsiveness, and automatisms. Seizure onset
in the posterior frontal lobes from the primary motor cortex
may have discrete motor manifestation that have a Jackso-
nian march that begins in the distal muscles of an extremity
and moves up the extremity. Patients with a seizure focus
located in the midline regions will often have involvement
of the supplementary motor cortex eliciting complex motor
manifestations such as dystonic posturing, vocalizations, or
speech arrest with variable loss of consciousness and minimal
postictal confusion. In addition, seizures originating from
the cingulate gyrus may also have autonomic features such
as tachycardia, tachypnea, pallor, and sweating (see Fig.
272). Seizure onset from dorsolateral frontal lobes may be
minimal or involve motor manifestations depending on the
extent of spread of the seizure activity. As noted previously,
patients with FLE seizures frequently do not exhibit interic-
tal EEG activity.
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560 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy

FIGURE 2721 Spikes (S) are noted in a standard PSG montage in all
derivations containing M1. These spikes are from a left temporal focus
(near M1). ECG = electrocardiogram.
F4-M1

C4-M1

O2-M1

S
E1-M2

E2-M2

ECG

50 V
1 sec

1 sec 1 sec

Fp1-F7

F7-T7

T7-P7

P7-O1

Fp2-F8

F8-T8

T8-P8

P8-O2

10 second window 30 second window

(4 seconds shown)

FIGURE 2722 Bipolar recording from the patient in Figure 2721 shows ictal activity of approximately 8 Hz in the left frontotemporal derivations. This confirms
the suspected left-sided focus noted in Figure 2721. The low amplitude in F7-T7 suggests that the focus is equidistant from both electrodes (see Fig. 278).

confused with a frightened expression and then scream.

NFLE Syndromes
Provini and colleagues13,14 described three general manifesta-
tions of NFLE including paroxysmal arousals (PAs), noctur-
nal paroxysmal dystonia (NPD), and episodic nocturnal
wandering (ENW) (Table 277). Paroxysmal arousals (PAs)
typically present during NREM sleep consisting of a stereo-
typical series of movements lasting 2 to 20 seconds in which
the individuals raise their head, sit up, and look around
Unlike typical sleep terrors, PAs can occur many times
during the night and are very stereotypical. NPD is char-
acterized by nocturnal coarse movements associated with
tonic spasms that often occur multiple times per night. The
episodes can be violent or be associated with vocalization.
Patients often move the arms and legs with cycling or kicking
movements and sometimes adopt a dystonic posture of the
limbs. Episodic nocturnal wanderings (ENWs) may present
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 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 561

TABLE 277
Manifestations of Nocturnal Frontal Lobe Epilepsy
PA NPD ENW
Frequency. Multiple times per night Multiple times per night Multiple times (13/night).
(mean 2). (mean 3).
Duration of episodes. Short 2040 sec. More prolonged (2598 sec). 31180 sec.
Patients sit up, look Arm and leg movements. Jump out of bed.
around, confused, Cycling. Wander.
often with loud Kicking. Vocalize.
scream. Dystonic posture (fencing). Violent behavior.
Pelvic thrusting.
Vocalization.
Violence can occur.
Can communicate at end of 100%. 44% can communicate at 100%.
seizure. end of episode.
Can communicate during 12/27. 10/59 during episode. None.
seizure.
Stereotypical or varied. Stereotyped. Stereotyped. Stereotyped, agitated
somnambulism.
Daytime seizures. No. 57% (49% secondarily 13%.
generalized seizures).
Brain structural abnormality. 0%. 24%. 5%.
NPD = nocturnal paroxysmal dystonia; ENW = episodic nocturnal wandering; PA = paroxysmal arousal.
Adapted from Provini F, Plazzi G, Tinuper P, et al: Nocturnal frontal lobe epilepsy. Brain 1999;122:10171031.

with symptoms similar to sleepwalking and sleep terrors.
Patients may jump out of bed, wander, vocalize, and show
violent behavior during sleep. Classically, treatment with
older anticonvulsants (in particular, carbamazepine) or
newer anticonvulsants such as levetiracetam at bedtime is
generally effective. However, some patients are refractory to
antiepileptic medications. It is important to note that a sig-
nificant proportion of patients with NFLE do have seizures
during wakefulness, generalization to tonic-clonic seizures,
and a demonstrable brain abnormality.
Familial NFLE
The original description was an autosomal dominant noc-
turnal frontal lobe epilepsy (ADNFLE) associated with a
missense mutation of the neuronal nicotinic acetylcholine
receptor (nAChR) alpha 4 subunit. Other mutations of the
nAChR gene system have been found and there is genetic
heterogeneity in families with ADNFLE. Four known loci
are 20q13.2, 15q24, 1q21, and 8p12.3-q12.3. Motor seizures
are frequent (nearly every night), often violent, occur in
clusters, and are brief (<1 min). The age of onset is variable
(2 mo56 yr). Ninety percent of patients present by age 20
years.
Supplemental Motor Area Epilepsy
Focal seizures arising from the supplementary motor area
(SMA), a region anterior to the motor cortex in the
midline, is a type of FLE that typically involves unilateral or
asymmetrical bilateral tonic posturing and may be associ-
ated with facial grimacing, vocalization, or speech arrest
(Fig. 2723). SMA seizures may be preceded by a somato-
sensory aura.1315 Complex automatisms such as kicking,
laughing, or pelvic thrusting may be present with respon-
siveness often preserved. A classic manifestation of SMA
epilepsy is the fencing posture with the head turned toward
an outstretched arm (head turns away from side of seizure
focus). Because consciousness is often well preserved and
postictal confusion minimal, these episodes are some-
times thought to be psychogenic. However, unlike psycho-
genic movements, SMA epilepsy episodes are typically brief
and stereotypical.
Parasomnia Versus NFLE
Information contrasting NFLE and NREM parasomnias
are listed in Table 278. In general, NFLE is associated
with greater frequency (episodes per month) and is more
likely to consist of multiple episodes in a given night.
The manifestations of NREM parasomnias also vary from
night to night whereas NFLE seizures have very stereo-
typical manifestations. They can be bizarre but they always
consist of the same activity. EEG is not that helpful in
many cases because approximately 40% to 50% of NFLE
patients have no interictal or ictal EEG findings (apart
from movement and muscle artifact associated with the
spells).
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562 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy

F7-F3

F3-Fz

Fz-F4

F4-F8

T3-C3

C3-Cz

Cz-C4

C4-T4

TC 0.1 HFF 60Hz 30 V

1 sec

FIGURE 2723 A nocturnal attack due to frontal lobe epilepsy from the supplemental motor area. Ictal EEG recording of a nocturnal
episode of frontal lobe epilepsy. The ictal EEG shows electrodecremental pattern associated with rhythmic low-amplitude 20- to 24-Hz
fast activity localized in the right midfrontal region (horizontal arrow) that evolved into activity of slower frequency and higher
amplitude as the clinical seizure began. HFF = high-frequency filter; TC = time constant. From Tachiban N, Shinde A, Ikeda A, et al:
Supplementary motor area seizure resembling sleep disorder. Sleep 1996;19:813.

Benign Epilepsy of Childhood with

Centrotemporal Spikes
Benign epilepsy of childhood with centrotemporal spikes
(BECTS), also known as rolandic epilepsy, accounts for 15%
to 20% of childhood epilepsy.10,17 The average age of onset
is 6 to 8 years (range 313). Seizures occur predominantly
during sleep and consist of oropharyngeal signs (hypersali-
vation and guttural sounds), arrest of speech with clonic
jerks, contraction of the mouth, and sometimes clonic jerks
of the arms or legs. The onset of seizure activity is about 20
minutes to 3 hours after bedtime. Consciousness is pre-
served in most cases unless there is secondary generaliza-
tion. Generalized seizures during sleep may occur. The EEG
typically shows centrotemporal or rolandic spikes or sharp
waves (Fig. 2724). In most patients, seizures resolve by
adulthood. If treatment is needed, the seizures respond well
to medication.
GENERALIZED EPILEPSY SYNDROMES
WITH NOCTURNAL SEIZURES
Generalized Epilepsy Syndromes
Primary generalized epilepsies include idiopathic GTC sei-
zures, AE seizures (petit mal), and juvenile myoclonic sei-
zures. GTC seizures consist of a sudden loss of consciousness,
a tonic phase of intense muscle contraction, and then a
clonic phasic consisting of bilaterally synchronous jerking of
the entire body. After the seizure, there is a postictal period
of disorientation lasting a variable amount of time.10,18 AE
seizures are manifested as a blank stare during which the
patient is unresponsive for 5 to 30 seconds. The characteristic
waking EEG pattern is a 3-Hz spike and wave pattern. AE
seizures start in childhood and rarely persist into adulthood.
The exception is when AE seizures begin after 9 to 10 years
of age. JME is a genetically determined condition involving
myoclonic jerks in the arms shortly after awakening. Primary
generalized seizures are sometimes called awakening epi-
lepsies because they commonly occur when the patient is in
a drowsy state upon awakening from sleep. Patients with
both AE and JME disorders also can have GTC seizures.
GTC seizures associated with these disorders usually occur
on awakening or shortly thereafter.
Generalized Seizures During or After Sleep
Epilepsy with GTC Seizures on Awakening
In this disorder, GTC seizures occur exclusively or predomi-
nantly shortly after awakening (regardless of the time of
awakening). Photic stimulation or sleep deprivation can pre-
cipitate GTC seizures. Myoclonic or AE seizures may coexist.
Complete control is usually possible with antiepileptic
medications.
Juvenile Myoclonic Epilepsy
JME is idiopathic (no demonstrable brain lesion) and has a
genetic basis with an abnormality on the short arm of chro-
mosome 6.10,19 Onset is in adolescence, peaking between ages
12 and 18. This is one of the more common forms of general-
ized epilepsy and consists of a combination of myoclonic
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 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 563

TABLE 278 have persistent GTC seizures requiring lifelong treatment.

Nocturnal Frontal Lobe Epilepsy Versus NonRapid Antiepileptic medications such as valproate are quite effec-
Eye Movement Parasomnias tive but lifelong treatment is usually needed owing to persis-
NREM
tence of GTC seizures. The interictal EEG in JME is
PARASOMNIA
characterized by diffuse polyspike and slow wave complexes
(CONFUSIONAL
of 4 to 6 Hz, usually maximal at the frontal electrodes. Neu-
AROUSALS, SLEEP
rologic examination and brain MRI are usually normal.
TERRORS,
SLEEPWALKING)
Absence Epilepsy
NFLE
AE is a genetically determined form of generalized epilepsy
Age at onset 14 10 (infancy <10 associated with brief spells, usually lasting less than 10
(yr SD) to adolescence) seconds, characterized by the abrupt cessation of ongoing
Gender Male/female 7/3 M=F activity, a blank stare, and abrupt return to awareness with
resumption of activity. AE seizures are precipitated by photic
Ictal EEG NREMsleep NREM sleep
stage N2 Stage N3 in
stimulation, hyperventilation, and drowsiness.10 The waking
Normal ictal EEG children EEG in AE is characterized by diffuse 3/sec spike and wave
44% activity (Fig. 2725), whereas the sleeping EEG can be
(higher if only associated with polyspike activity. AE responds well to
scalp electrodes treatment and seizures may decrease as patients age. Unlike
used) complex partial seizures (which can also affect the senso-
Normal interictal rium), AE is not associated with an aura or postictal
EEG 51% confusion.
Movement Violent, Complex,
seminology stereotypical nonstereotypical Lennox-Gastaut Syndrome
This syndrome is associated with generalized tonic, atonic,
Family history of 39% 6296%
episodes and atypical AE seizures.10 There is typically a slow back-
ground on interictal EEG with slow (usually 22.5 Hz) spike
Episode frequency/ 20 11 <14 and wave complexes during wake and generalized fast
mo
rhythms during sleep (Fig. 2726). Affected individuals have
Episode frequency/ 3 3 (higher with 1 mental retardation.
night PA, NPD)
Episode duration 2 sec3 min 15 sec30 min ICTAL EFFECTS ON SLEEP
Clinical course Increased Tend to resolve
Nocturnal epilepsy can impair sleep quality and result in
frequency
complaints of daytime sleepiness or insomnia. Up to 68% of
Triggering factors None in 78% Sleep deprivation, patients with epilepsy complain of daytime sleepiness and
alcohol, febrile 39% complain of insomnia.10,11,19,20 Partial and primary gen-
illness eralized seizures can be associated with sleep fragmentation,
Autonomic Very common Yes in sleep terrors increased sleep stage shifts, and decreased sleep efficiency.
activation (tachycardia) Although antiepileptic drugs (AEDs) can also impair sleep,
Episode onset after Any time First third of night the sleep of patients with nocturnal epilepsy is usually better
sleep onset in children on AEDs than without AEDs. That is, seizure control
improves sleep quality.
Effect of treatment Carbamzaepine N/A
abolished (20%)
or improved ANTIEPILEPTIC DRUGSEFFECTS ON SLEEP
episodes (50%)
The effects of common AEDs1921 on sleep are listed in
EEG = electroencephalogram; N/A = not applicable; NFLE = nocturnal frontal
lobe epilepsy; NPD = nocturnal paroxysmal dystonia; NREM = nonrapid eye Table 279. Published information on this topic is somewhat
movement; PA = paroxysmal arousal; SD = standard deviation. conflicting and often based on small studies. For most
Adapted from Provini F, Plazzi G, Tinuper P, et al: Nocturnal frontal lobe patients, the benefits of seizure control on sleep outweigh
epilepsy. Brain 1999;122:10171031.
side effects of AEDs.

seizures on awakening, GTC seizures, and AE seizures. The

myoclonic seizures occur in clusters on awakening or shortly
thereafter. Patients may not seek medical evaluation until
after the first associated GTC seizure. The myoclonic seizure
may subside during adulthood, but patients often
EPILEPSY AND OBSTRUCTIVE SLEEP APNEA
One study in 2003 of unselected adult epilepsy patients
found an obstructive sleep apnea (OSA) prevalence of 10.2%
(15.4% in men and 5.4% in women).22 An even
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564 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy

50 V
1 sec

Fp1-F3

F3-C3

C3-P3

P3-O1

Fp2-F4

F4-C4

C4-P4

P4-O2

FIGURE 2724 An example of EEG tracing with interictal activity in a patient with benign epilepsy of childhood with centrotemporal
spikes (BECTS). Note the spikes prominent in the frontocentral derivations on the left. There is a phase reversal at C3. From Chokroverty
S, Quinto C: Sleep and epilepsy. In Chokroverty S (ed): Sleep Disorders Medicine. Boston: Butterworth Heinemann, 1999, p. 711.

1 sec

F4-M1

C4-M1

O2-M1

E1-M2

E2-M2

Chin

FIGURE 2725 Three-Hz spike and wave complexes in a patient with absence epilepsy.

higher frequency has been found in patients with refractory
epilepsy. Therefore, a high index of suspicion is indicated
when patients with epilepsy report disturbed sleep and
snoring. A randomized, pilot-controlled study of continu-
ous positive airway pressure (CPAP vs. sham) in a group of
patients with medically refractory epilepsy and coexistent
OSA found a trend for improvement in nocturnal seizures
frequency.23 A 50% or greater reduction in seizure frequency
was noted in 28% of CPAP patients and 15% in the sham
group (P = .40). Further large studies are needed, but cer-
tainly in individual patients, effective treatment of OSA may
improve seizure control. The etiology of the benefit of CPAP
treatment is not clear. It is known that prior sleep deprivation
or disturbance can worsen seizure control. Therefore,
improvements in sleep with CPAP treatment may be one
mechanism by which seizure control is improved.
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 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy 565

Fp1-F7
100 V
F7-T7
T7-P7
P7-O1
Fp2-F8

F8-T8
T8-P8
P8-O2
Fp1-F3

F3-C3
C3-P3
P3-O1
Fp2-F4

F4-C4
C4-P4
P4-O2
Fz-Cz
Cz-Pz
1 sec

FIGURE 2726 A tracing from a patient with slow spike and wave activity and the Lennox-Gastaut syndrome. From Foldvary-Schaefer N,
Grigg-Damberger M: Sleep and epilepsy. Sleep Med Clin 2008;3:450.

TABLE 279 CLINICAL REVIEW QUESTIONS

Effects of Common Antiepileptic Drugs on Sleep 1. Which of the following characterizes the propensity of
POSITIVE NEGATIVE nocturnal seizures?
A. NREM > REM > wake.
Barbiturates Decreased sleep Decreased REM
(phenobarbital) latency B. Wake > REM > NREM.
Increased sleep C. NREM > wake > REM.
efficiency D. Wake > NREM > REM.
Increased stage N2
Carbamazepine None known Decreased REM? 2. What is the most frequent type of nocturnal partial
seizure?
Phenytoin Decreased sleep Increased arousal
latency Increased stage N1 A. TLE.
Decreased REM B. NFLE.
Valproic acid None known Increased stage N1 C. AE.
D. JME.
Gabapentin Increased stage N3 None
Decreased
3. Phase reversal is helpful to:
arousals
A. Identify a transient as epileptiform.
Levetiracetam Increased stage N3 None
B. Localize a transient or seizure focus.
REM = rapid eye movement.
C. A and B.
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566 Chapter 27 Clinical Electroencephalography and Nocturnal Epilepsy
4. Which of the following statements about POSTS is not
true?
A. They are positive.
B. They have an occipital location.
C. They occur during wake.
D. They are sharp wave.
5. Which of the following is NOT true about mu rhythm?
A. They are 8 to 13 Hz.
B. They are most prominent in occipital derivations.
C. They are attenuated by contralateral arm movement.
D. They have archiform morphology.
Answers
1. C. NREM > wake > REM. During NREM, seizures out
of N2 are more common.
2. A. Although FLE is more likely to occur during the night
compared to during the day, NTLE is more common than
NFLE as TLE is much more common than FLE. AE is a
generalized epilepsy. JME is manifested as myoclonic
jerks soon after awakening.
3. B. Phase reversal is helpful for localization but does not
imply abnormality.
4. C. POSTS occur during NREM sleep.
5. B. Mu rhythm is more prominent in the central
derivations.
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Sleep Medicine, 2007.
4. Fisch BJ: Spehlmans EEG Primer. New York: Elsevier, 1991.
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7. Foldvary N, Caruso AC, Mascha E, et al: Identifying montages
that best detect electrographic seizure activity during polysom-
nography. Sleep 2000;23:19.
8. Foldvary N: Video-encephalography/polysomnography for
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Carsakadon MA (eds): Sleep Medicine. Philadelphia: Hanley &
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onset site. Neurology 2001;56:14531459.
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epilepsy. Brain 1999;122:10171031.
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area seizure resembling sleep disorder. Sleep 1996;19:811816.
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Chapter Points
Parasomnias are defined as undesirable physical
events or experiences that occur during entry to sleep,
within sleep, or during arousals from sleep.
The indications for evaluation of patients with a
suspected parasomnia with PSG include (1) potentially
violent or injurious behavior, (2) behavior that is
extremely disruptive to household members, (3) the
parasomnia results in a complaint of excessive
sleepiness, and (4) the parasomnia is associated with
medical, psychiatric, or neurologic symptoms or
findings.
If a PSG is indicated for evaluation of a patient for a
suspected parasomnia, then use of video PSG
(synchronized video and audio) with additional EEG
electrodes is recommended.
The NREM parasomnias include confusional arousals
(awakening with confusion), sleepwalking (ambulation
during sleep), and sleep terrors (awakening with loud
scream and intense fear). In children, NREM
parasomnias occur out of stage N3 (first part of the
night) but in adults can occur out of stages N1 or N2
during any part of the night. Approximately 6070%
of adults with a NREM parasomnia experienced one
or more NREM parasomnias in childhood.
The REM parasomnias include the RBD, nightmare
disorder, and recurrent sleep paralysis.
Diagnostic criteria for RBD include
REM sleep without atonia: the EMG finding of
excessive amounts of sustained or intermittent
elevation (transient muscle activity) of submental
EMG tone or excessive phasic submental or (upper
or lower) limb EMG twitching.
At least one of the following is present:
Sleep-related injurious, potentially injurious, or
disruptive behavior by history.
Abnormal REM sleep behavior documented
during PSG monitoring.
Absence of EEG epileptiform activity during
REM sleep (unless RBD can be clearly distinguished
from any concurrent REM sleep-related seizure
disorder).
Chapter 28
Parasomnias
The sleep disturbance is not better explained by
another sleep disorder, medical or neurologic
disorder, mental disorder, or substance use disorder.
Treatments for RBD include environmental
precautions, clonazepam, and/or melatonin (often in
high doses).
The overlap parasomnia consists of manifestations of
both an NREM parasomnia and RBD.
RBD has been associated with narcolepsy, Parkinsons
disease, dementia with Lewy bodies, multiple system
atrophy, multiple sclerosis, and certain medications. A
significant proportion of patients with idiopathic RBD
later develop Parkinsons disease.
Nocturnal seizures may mimic parasomnias
especially frontal lobe epilepsy. Features favoring
epilepsy over a parasomnia include stereotypical
behavior (same manifestations each time) and more
than one episode per night.
The sleep-related eating disorder is manifested by
eating and drinking during the main sleep period and
is associated with a variable degree of alertness and
recall for the eating behavior. The behavior must be
associated with one or more of several manifestations
including eating peculiar food items, associated with
insomnia due to sleep disturbance from the eating
episodes, sleep-related injury, dangerous behaviors in
pursuit of food, morning anorexia, or adverse
consequences of binge eating.
Catathrenia is characterized by a deep inspiration and
long expiratory groan, most commonly during REM
sleep.
Secondary enuresis is defined as the onset of
enuresis in a patient who has previously been dry
for at least 6 months. The diagnosis of OSA should
be considered in all children who snore and have
secondary enuresis.
The exploding head syndrome is characterized
by a sudden loud imagined noise or sense of
violent explosion in the head occurring as the
patient is falling asleep on waking during the night.
The event is painless but patients usually awaken
with fright.
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568 Chapter 28 Parasomnias
Determining a cause for abnormal movements or behavior
during sleep is often a challenging problem for sleep physi-
cians. A parasomnia is a motor, verbal, or experiential phe-
nomenon that occurs in association with sleep (at sleep
onset, during sleep, or after arousal from sleep) and is often
undesirable. The term parasomnia comes from a combina-
tion of para from the Greek prefix meaning alongside of
with the Latin word somnus meaning sleep. In the usual
clinical setting, the term refers to undesirable events. In the
International Classification of Sleep Disorders, 2nd edition
(ICSD-2),1 parasomnias are defined as undesirable physical
events or experiences that occur during entry to sleep, within
sleep, or during arousals from sleep.
Evaluation of nocturnal spells or unusual behavior
begins with a detailed history of the nature, age of onset, and
time of night of the episodes. Factors (sleep deprivation and
medications) that may have affected the behaviors should
be explored. A neurologic examination should be performed
to rule out associated neurologic disorders. Not all para-
somnias require evaluation by polysomnography (PSG). The
indications for evaluation with PSG include24: (1) poten-
tially violent or injurious behavior, (2) the behavior is
extremely disruptive to household members, (3) the para-
somnia results in a complaint of excessive sleepiness, and (4)
the parasomnia is associated with medical, psychiatric, or
neurologic symptoms or findings.
Video PSG (usually with synchronized video and audio)
is the recommended method of evaluating parasomnias.
Today, virtually all digital PSG equipment manufacturers
offer synchronized video and audio with their digital PSG
recording systems. Additional electroencephalogram (EEG)
electrodes are commonly used to monitor patients with a
suspected parasomnia to improve the ability to detect inter-
ictal or seizure activity. Additional arm electromyogram
(EMG) derivations (flexor digitorum) are often performed
in addition to right and left tibialis anterior (leg) EMGs to
detect transient muscle activity (TMA; phasic muscle activ-
ity) during rapid eye movement (REM) sleep. One problem
with monitoring parasomnias is that they frequently do not
occur every night. Multiple nights of video PSG may be
needed.
The ICSD-2 lists a number of parasomnias (Box 281).1
Some parasomnias are associated with nonrapid eye move-
ment (NREM) sleep, some with REM sleep, and some are
classified as other parasomnias because they can occur
during either NREM or REM sleep or during wakefulness
soon after arousal from sleep.
NREM PARASOMNIAS
The NREM parasomnias include (1) confusional arousals,
(2) sleepwalking, and (3) sleep terrors.58 There is some
overlap in these parasomnias and individual patients may
manifest behavior consistent with all three types of NREM
parasomnias on different nights. Although not listed in the
major ICSD-2 diagnostic categories, sleep-related sexual
behavior and sleep-related violence are considered variants
BOX 281
Classification of Parasomnias
A. DISORDERS OF AROUSAL FROM NREM SLEEP
1. Confusional arousals
2. Sleepwalking
3. Sleep terrors
B. DISORDERS USUALLY ASSOCIATED WITH REM SLEEP
1. REM sleep behavior disorder (including parasomnia
overlap disorder and status dissociatus)
2. Recurrent isolated sleep paralysis
3. Nightmare disorders
C. OTHER PARASOMNIAS
1. Sleep-related dissociative disorders
2. Sleep enuresis
3. Sleep-related groaning (catathrenia)
4. Exploding head syndrome
5. Sleep-related hallucinations
6. Sleep-related eating disorder
7. Parasomnia, unspecified
8. Parasomnia due to drug or substance
9. Parasomnia due to medical condition
NREM = nonrapid eye movement; REM = rapid eye movement.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
of the confusional arousalsleepwalkingsleep terrors
spectrum.
Confusional Arousals
Confusional arousals usually occur from stage N3 in the first
part of the night but can occur after an arousal from NREM
sleep at any hour. In children, confusional arousals usually
occur out of stage N3. In adults, confusional arousals may
also occur out of stage N1 or stage N2.1,5 Amnesia for the
event is common. Confusional arousal events are brief and,
because of amnesia, often go unnoticed unless reported by
the bed partner. During awakening, behavior may be inap-
propriate (especially forced awakening) and even violent.
Although behaviors are usually simple (movements in bed,
thrashing about, vocalization, or inconsolable crying), they
can be more complex. There is frequently an overlap between
confusional arousals and sleepwalking. In contrast to sleep
terrors, patients with confusional arousals do NOT exhibit
autonomic hyperactivity or signs of fear or emit a blood-
curdling scream.
Prevalence
Confusional arousal episodes are common in children aged
younger than 13 years with a prevalence of 17%. In older
individuals (>15 yr of age), the prevalence is much lower
(34%). Men and women are equally affected.
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Precipitating and Predisposing Factors
Common factors precipitating confusional arousals include
sleep deprivation, bipolar and depressive disorders, obstruc-
tive sleep apnea (OSA), and rotating shift/night shift work.
There is frequently a family history of similar events in
related individuals. In children, the confusional arousals
usually resolve after age 5 years.
Variants of Confusional Arousals
The ICSD-2 lists two variants of confusional arousals1:
1. Severe morning sleep inertia (sleep drunkenness): This is
a variant of confusional arousal in adults and arousal is
often out of stage N2 or stage N1 sleep.
2. Sleep-related sexual behaviors: These include masturba-
tion or sexual assault on adults or minors (sleep sex). This
entity is described in more detail later in the Sleepwalk-
ing (Somnambulism) section.
PSG Findings during Confusional Arousals
The EEG during arousal may show persistent delta activity,
theta activity, or diffuse poorly reactive alpha activity.
Increased chin EMG activity is typical and EMG artifact in
the EEG derivations is common (Fig. 281). At event onset,
the heart rate increases.
Diagnosis of Confusional Arousals
The ICSD-2 diagnostic criteria for confusional arousals are
listed in Box 282. Note that PSG findings are not part of the
criteria. Most patients with confusional arousals will not
require PSG unless the parasomnia has resulted in injury, the
potential for injury, or if treatment is being considered.
Differential Diagnosis of Confusional Arousals
The differential diagnosis of confusional arousals, sleepwalk-
ing, and sleep terrors is discussed later in this chapter.
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin EMG
FIGURE 281 A 30-second epoch shows a confusional arousal from stage N3 in a 45-year-old adult. There was no evidence of change in airflow before the episode. Note the
absence of any change in the electroencephalogram (EEG) or electromyogram (EMG) derivations before the arousal. The patient abruptly sat up and looked around, appearing
confused.
Chapter 28 Parasomnias 569
Treatment of Confusional Arousals
Usually, no treatment is needed. There are no controlled
studies concerning treatment of confusional arousals. Ben-
zodiazepine receptor agonists (BZRAs) and tricyclic antide-
pressants (TCAs) have been used.46
Sleepwalking (Somnambulism)
Sleepwalking is defined as a series of complex behaviors that
are initiated during sleep (usually stage N3) and result in
ambulation (Boxes 283 to 285). Activity can vary from
simply sitting up in bed to walking. Patients usually are dif-
ficult to awaken during these episodes and, if awakened, are
confused. Of interest, the eyes are usually open (wide open
and glassy-eyed) during sleepwalking,1,3 but patients may be
clumsy in their movements. Talking during sleep (somnilo-
quy) can occur simultaneously. In children, sleepwalking
usually occurs during the first third of the night, when stage
N3 is present. However, studies in adults have recorded epi-
sodes beginning in stage N1 or N2 sleep and frequently in
the second half of the night.58 Episodes of sleepwalking in
children are rarely violent, and movements often are slow. In
BOX 282
Confusional ArousalsDiagnostic Criteria
A. Recurrent mental confusion or confusional behavior
occurs during arousal or awakening from nocturnal
sleep or a daytime nap.
B. The disturbance is not better explained by another sleep
disorder, medical or neurologic disorder, mental
disorder, or substance use disorder.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
100 V
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570 Chapter 28 Parasomnias
BOX 283
Sleepwalking (Somnambulism)
Diagnostic Criteria
A. Ambulation occurs during sleep.
B. Persistence of sleep, an altered state of
consciousness, or impaired judgment during
ambulation is demonstrated by at least one of the
following:
i. Difficulty in arousing the person.
ii. Mental confusion when awakened from an episode.
iii. Amnesia (complete or partial) for the episode.
iv. Routine behaviors that occur at inappropriate times.
v. Inappropriate or nonsensical behaviors.
vi. Dangerous or potentially dangerous behaviors.
C. The disturbance is not better explained by another sleep
disorder, medical or neurologic disorder, mental
disorder, or substance use disorder.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
BOX 284
Predisposing Factors for Sleepwalking
and Sleep Terrors
Genetic
Risk of sleepwalking
22% if neither parent affected.
45% if one parent affected by sleepwalking.
60% if both parents have history of sleepwalking.
65% if twin has sleepwalking.
Sleep deprivation.
Fever, life stress, novel bedroom.
Untreated obstructive sleep apnea, or with initial CPAP
treatment.
CNS diseasemigraines, head injury, encephalitis.
Alcohol abuse.
Medications
Zolpidem.
Lithium carbonate.
Phenothiazines.
CNS = central nervous system; CPAP = continuous positive airway pressure.
adults, sleepwalking episodes can be more complex, fren-
zied, violent, and longer in duration. Episodes of sleepwalk-
ing may be terminated by the patient returning to bed or
simply lying down and continuing sleep out of bed. Patients
are difficult to arouse during sleepwalking episodes. When
aroused during sleepwalking, patients are typically very con-
fused. In addition, there is total amnesia for the sleepwalking
episodes (see Box 284).
Epidemiology and Familial Pattern of Sleepwalking
Sleepwalking can occur as soon as children can walk but
peaks between the ages of 4 and 8 occurring in between 10%
and 20% of children. The onset of sleepwalking can also
BOX 285
Sleepwalking Facts
About 6070% of adults with sleepwalking had episodes
as children.
Sleepwalking classically occurs during stage N3 in the
first part of the night.
Sleepwalking in some adults can occur in stage N1 or N2
sleep and in the second half of the night.
The persistence of sleepwalking into adulthood or
re-emergence of sleepwalking does NOT always imply
underlying psychopathology. However, a significant
proportion may have current or past psychopathology.
Prior sleep deprivation with resulting slow wave sleep
rebound (as with nasal CPAP treatment for OSA) can
trigger episodes of sleepwalking.
Treatment of sleepwalking
Environmental precautions.
Avoid sleep deprivation.
Clonazepam and other BZRAs.
TCAs.
SSRIs.
BZRAs = benzodiazepine receptor agonists; CPAP = continuous positive
airway pressure; OSA = obstructive sleep apnea; SSRIs = selective serotonin
reuptake inhibitors; TCAs = tricyclic antidepressants.
occur in adulthood. However, most adult sleepwalkers had
episodes during childhood (6070% of adults with sleep-
walking exhibited this parasomnia during childhood). Sleep-
walking usually disappears in adolescence. One study of 100
patients with sleep-related injury found that 33% with sleep-
walking had an age of onset after age 16, and 70% had epi-
sodes arising from both stages N1 and N2 as well as stage
N3. The sleepwalking behaviors were variable in duration
and intensity.6
Familial, Precipitating, and Predisposing Factors
A number of predisposing and precipitating factors for
NREM parasomnias (including sleepwalking) have been
identified in children and adults.1,8,9 There is a definite famil-
ial role in the development of sleepwalking (see Box 284).
If one or both parents have a history of sleepwalking, the
risk of a child developing sleepwalking episodes is greatly
increased. Fever, sleep deprivation, and certain medications
(e.g., zolpidem and other BZRAs, phenothiazines, TCAs,
lithium) can precipitate the events. Sleepwalking during slow
wave sleep rebound has been reported in a patient with OSA
treated with nasal continuous positive airway pressure
(CPAP).10 Untreated sleep apnea can also be a predisposing
factor, given the frequent arousals associated with respira-
tory events in this disorder. Effective treatment of sleep
apnea can reduce the frequency of sleepwalking in some
patients.11
The relationship between mental illness and adult NREM
parasomnias is a topic of controversy.6,12 Some have sug-
gested that persistence of sleepwalking into adulthood is a
manifestation of underlying psychopathology. However,
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Schenck and coworkers6 found evidence of prior or cur-
rent psychopathology in only about 48% of adults with
sleepwalking/sleep terrors who underwent PSG monitoring
for sleep-related injury. Therefore, the adult sleepwalking
patients were equally as likely not to have psychopathology
as to have this problem. In addition, there was typically no
association between sleepwalking/sleep terrors and any con-
current psychopathology with respect to onset, clinical
course, or treatment response.12 However, because mental
illness and medication used to treat mental illness can
disturb sleep, sleepwalking could well occur or re-emerge in
patients with active mental illness.
PSG in Sleepwalking
Although PSG is rarely performed to evaluate cases of sleep-
walking, the classic finding is a sudden arousal occurring in
stage N3 sleep (Fig. 282). During the prolonged arousal,
there usually is tachycardia and often persistence of slow
wave EEG activitydespite the presence of high-frequency
EEG activity and an increase in EMG amplitude. Analysis of
a large group of patients with sleepwalking and sleep terrors
found that there was no prearousal buildup of delta activ-
ity, increase in heart rate, or prearousal increase in chin
EMG. Postarousal, the EEG showed three patterns: (1)
diffuse rhythmic (synchronized) delta activity, (2) diffuse
delta and theta activity, and (3) prominent alpha and beta
activity.13 The heart rate is often noted to increase at the onset
of the event.
Diagnosis of Sleepwalking
Diagnostic criteria for sleepwalking are listed in Box 283
and do not require PSG findings. The ICSD-2 major criteria
for a diagnosis of sleepwalking1 include (A) ambulation
during sleep and (B) evidence of persistent sleep, altered
consciousness, or impaired judgment during ambulation.
100 V
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
FIGURE 282 A 60-second tracing shows an episode of sleepwalking that occurred out of stage N3 in a 5-year-old boy. Note the persistence of slow wave activity during the
arousal and subsequent body movements. The patient abruptly aroused, sat up, and left the bed.
Chapter 28 Parasomnias 571
Evidence for an altered state of consciousness includes dif-
ficulty in arousing the person, mental confusion when awak-
ened from an episode, amnesia (complete or partial) for the
episode, and abnormal behaviors. Abnormal behaviors
include routine behaviors that occur at inappropriate times,
inappropriate or nonsensical behaviors, and dangerous or
potentially dangerous behaviors.
Differential Diagnosis of Sleepwalking
The differential diagnosis of sleepwalking is discussed with
confusional arousal and sleep terrors in a later section.
Sleep-Related Sexual Behavior
and Sleep-Related Violence
The main complications of sleepwalking are social embar-
rassment and danger of self-injury or injury to others.
Violent behavior (self-mutilation or homicide) and sexual
assault (sleep sex) have been reported in association with
sleepwalking episodes. Sleep-related sexual behavior or
sex-somnia14,15 is a parasomnia in which sexual behavior
occurs with limited awareness during the act, relative unre-
sponsiveness to the external environment, and amnesia for
the event. The behaviors range from sexual vocalizations to
intercourse. These actions may include behaviors very atypi-
cal for the individual (e.g., anal intercourse). In contrast to
typical sleepwalking, these events can exceed 30 minutes.
Sleep-related violence occurs in a state consistent with
sleepwalking/sleep terrors and is associated with an emotion
of fear or anger. The violent behavior may be directed at
individuals in close proximity or those who confront the
individual during the parasomnia.16,17 The patient may either
awaken or go back to sleep but typically has amnesia for the
event. The violence is often atypical for the individual. Most
cases of sleep-related violence occur in middle-aged men
with a history of prior sleepwalking.
out of bed here
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572 Chapter 28 Parasomnias
Sleep Disorders and the Law
Automatisms are defined as involuntary behavior over
which an individual has no control. The behavior may be out
of character and the individual may have no recall for the
events. The sleep automatisms likely to result in injurious
behavior include NREM parasomnias, sleep-related disso-
ciative disorders (SRDDs; discussed in a later section), and
sleep-related epilepsy. An important legal question for con-
sideration is the presence or absence of criminal intent.
When criminal action is taken against the violent sleep-
walker, sleep medicine physicians may be called as expert
witnesses.16,17 There are guidelines for expert witness qualifi-
cations and testimony.17 In addition, criteria have been pro-
posed to assist in determination of the putative role of an
underlying sleep disorder17 (Box 286).
Treatment of Sleepwalking
The treatment of sleepwalking includes environmental pre-
cautions (e.g., closed doors and windows, sleeping on the
first level) and avoidance of precipitating causes such as
sleep deprivation as well as reassurance. If the episodes are
determined to require medication, benzodiazepines, TCAs,
or selective serotonin reuptake inhibitors (SSRIs) may be
tried. Clonazepam 0.5 to 2.0 mg qhs or temazepam 30 mg
qhs are commonly prescribed. Medications should be given
early enough before bedtime so that sleepwalking in the
first slow wave cycle is prevented. In one study of patients
with self-injurious behavior, bedtime clonazepam was suc-
cessful in controlling sleep terrors/sleepwalking in greater
than 80% of cases.6 However, not all studies have found
clonazepam to be this effective. Another study of treatment
of patients with sleepwalking found that those with any
degree of sleep apnea had fewer sleepwalking episodes if
sleep apnea was effectively treated.11 Conversely, treatment
BOX 286
Guidelines for Determination of the Putative Role
of a Sleep Disorder in a Violent Act
1. A reason to suspect a sleep disorder exists (history, PSG
findings).
2. Duration of episodes is brief (min)can be much longer.
3. Behavior is abrupt, immediate, impulsive, without
apparent motivation, no premeditation.
4. Victim is someone who happened to be present.
5. Immediately upon return of consciousnesshorror at
event, no attempt to escape or conceal act.
6. Some degree of amnesia for event.
7. In case of sleepwalking, the act must:
a. Occur upon awakening, usually at least 1 hour after
sleep onset.
b. Occur on attempt to awaken the patient.
c. Be potentiated by alcohol ingestion, sedative/
hypnotic administration, or prior sleep deprivation.
PSG = polysomnography.
Adapted from Mahowald MW, Schenck CH: Parasomnias: sleep walking and
the law. Sleep Med Rev 2000;4:321339.
with benzodiazepines was NOT effective in those without
sleep-related breathing problems.11 A recent systematic
review of sleepwalking treatments found that no large con-
trolled studies of treatment for sleepwalking have been
reported.18
Sleep Terrors
Sleep terrors, also called night terrors or pavor nocturnus,
consist of sudden arousal, usually from stage N3 sleep,
accompanied by a blood-curdling scream or cry and mani-
festations of severe fear (behavioral and autonomic) (Boxes
287 and 288). The affected individual typically is confused,
diaphoretic, and tachycardic, and he or she frequently sits up
in bed. It is difficult or impossible to communicate with a
BOX 287
Sleep TerrorsDiagnostic Criteria
A. Sudden episode of terror occurs during sleep, usually
initiated by a cry or loud scream that is accompanied by
autonomic nervous system activation and behavioral
manifestations of intense fear.
B. At least one of the following is present:
i. Difficulty in arousing the person.
ii. Mental confusion when awakened from episode.
iii. Amnesia (complete or partial) for the episode.
iv. Dangerous or potentially dangerous behaviors.
C. The disturbance is not better explained by another sleep
disorder, medical or neurologic disorder, mental
disorder, medication use, or substance use disorder.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
BOX 288
Sleep Terror Facts
In children, sleep terrors occur out of stage N3 in the first
part of night.
In adults, sleep terrors can occur from stage N2 sleep.
Patients may manifest both sleep terrors and
sleepwalking.
In contrast to confusional arousals, patients with sleep
terrors have profound autonomic hyperactivity and
manifestations of fear.
Unlike RBD or nightmares, patients with sleep terrors do
not relate dream mentation associated with the event,
The persistence of sleep terrors into adulthood,
re-emergence of sleep terrors in adulthood, or onset of
sleep terrors in adulthood is not necessarily evidence that
psychopathology is present.
Sleep terrors have been described in adults during nasal
CPAP treatment of OSA.
CPAP = continuous positive airway pressure; OSA = obstructive sleep apnea;
RBD = rapid eye movement sleep behavior disorder.
DaneshGroup.com

person having a sleep terror, and total amnesia for the event
is usual. Patients may sleepwalk during episodes of sleep
terrors. Thus, many consider sleepwalking and sleep terrors
to be one syndrome with a spectrum of manifestations.
Epidemiology
Sleep terrors typically occur in prepubertal children (3%)
and subside by adolescence; they are uncommon in adults.
Sleep terrors rarely begin in adulthood. As noted previously,
one study of patients with sleep terrors/sleepwalking evalu-
ated for sleep-related injury found that 48% had evidence of
current or prior psychopathology.6 However, adults with
sleep terrors are just as likely not to have related psychopa-
thology as to have this problem. In addition, sleep terrors/
sleepwalking and any concurrent psychopathology are often
not closely associated with respect to their onset, clinical
course, or treatment response.12
Precipitating and Predisposing Factors
Stress, febrile illness, sleep deprivation, and heavy caffeine
intake have been identified as inciting agents for sleep terrors.
Stressful events and sleep deprivation can sometimes pre-
cipitate re-emergence of problems that were present in child-
hood. Slow wave sleep rebound, such as occurs with nasal
CPAP treatment of OSA, has also been associated with epi-
sodes of sleep terrors.19
PSG Findings Associated with Sleep Terrors
PSG is usually not required to evaluate sleep terrors unless
the episodes are frequent, are violent, or have the potential
to result in self-injury. When PSG is performed, video PSG
is indicated. If seizures are suspected, a complete clinical
EEG montage is needed. When a sleep terror is captured, it
appears as a sudden arousal from slow wave sleep. The chin
EMG amplitude is greatly increased, and alpha waves are
present; however, persistent slow wave activity is also noted.
Diagnosis of Sleep Terrors
The ICSD-2 criteria are listed in Box 287. The diagnostic
criteria include an episode of terror usually initiated by a
loud scream that is accompanied by autonomic nervous
system activation and behavioral manifestations of intense
TABLE 281
Comparison of the Characteristics of NonRapid Eye Movement Parasomnias
CONFUSIONAL AROUSAL
Onset Stage N3 children
Stage N2, N3 adults
Autonomic hyperactivity No
Loud scream No
Confusion during episode Yes
Amnesia (partial or complete) Yes
Chapter 28 Parasomnias 573
fear. In addition, evidence of an altered state of conscious-
ness including difficulty in arousing the person, mental con-
fusion after awakening, and partial or complete amnesia for
the event is required.
Treatment of Sleep Terrors
The treatment of sleep terrors is similar to that for confu-
sional arousal and sleepwalking. If the episodes of sleep
terrors are infrequent, treatment beyond simple environ-
mental precautions is unnecessary. The medications used for
sleepwalking have also been used for sleep terrors. Benzodi-
azepines, TCAs, and SSRIs have been used with some success.
No controlled study has evaluated treatments for sleep
terrors.18 Avoidance of inciting agents is recommended (see
Box 284).
Differential Diagnosis of NREM Parasomnias
Comparison of characteristics of confusional arousal, sleep
terrors, and sleepwalking are listed in Table 281. The dif-
ferential diagnosis of these NREM parasomnias includes the
rapid eye movement sleep behavior disorder (RBD), night-
mare disorder, nocturnal seizure activity, the posttraumatic
stress disorder (PTSD), and nocturnal panic attacks. Night-
mare disorders (also called dream anxiety attacks) and RBD
occur during REM sleep and are more common in the
second part of the night. Body movements during RBD can
result in patients leaving the bed but rarely the bedroom.
RBD usually does not begin until after age 40 and has a
strong male predominance. When patients are awakened
from RBD episodes they are less confused than in NREM
parasomnias. Differentiation of NREM parasomnias from
partial complex seizures is difficult without complete EEG
monitoring. Seizures tend to be more stereotypical and may
occur during the day. Patients with nightmares, the PTSD,
and RBD typically can relate complex dream mentation that
promoted the event. In sleep-related panic attacks,20 the
patient can awaken from NREM sleep following arousals and
develop autonomic activation and fear. However, in contrast
to the NREM parasomnias, patients with panic attacks do
not have confusion, nonresponsiveness, amnesia, or dra-
matic motor activity. Panic attacks occur during wakefulness
and tend to build in intensity over several minutes.
SLEEPWALKING SLEEP TERRORS
Same Same
No Prominent
No Yes
Yes Yes
Yes Yes
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574 Chapter 28 Parasomnias
PARASOMNIAS USUALLY ASSOCIATED WITH
REM SLEEP (STAGE R)
Parasomnias usually associated with REM sleep (stage R)
include RBD, recurrent isolated sleep paralysis, and night-
mare disorders (see Box 281). RBD has two variants: overlap
parasomnia and status dissociatus (SD).
REM Sleep Behavior Disorder (RBD;
Including Variants)
RBD is characterized by a loss of the normal muscle atonia
associated with REM sleep with dream-enactment behavior
(oneirism) that is often violent in nature (Box 289).6,2124
Dreams are acted out. Limb and body movements often are
violent (e.g., hitting a wall, kicking) and may be associated
with emotionally charged utterances. The movements can be
related to dream content (kicking an attacker), but the
patient may or may not remember associated dream mate-
rial when awakened during an episode. Serious injury to the
patient or the bed partner can result from these episodes,
which typically occur one to four times a week. Because the
episodes occur during REM sleep, they are most common
during the early morning hours (the second half of the
night). There is a strong male predominance and most cases
occur after age 50.
Epidemiology of RBD
The median age of onset is about 50 years, and a milder
prodrome of sleep talking, simple limb-jerking, or vividly
violent dreams may precede the full-blown syndrome. RBD
can be idiopathic or associated with a number of neurode-
generative disorders and medications2528 (Box 2810).
BOX 289
Rapid Eye Movement Sleep Behavior Disorder
Diagnostic Criteria
A. Presence of REM sleep without atonia: the EMG finding
of excessive amounts of sustained or intermittent
elevation of submental EMG tone or excessive phasic
submental or (upper or lower) limb EMG twitching.
B. At least one of the following is present:
i. Sleep-related injurious, potentially injurious, or
disruptive behavior by history.
ii. Abnormal REM sleep behavior documented during
PSG monitoring.
C. Absence of EEG epileptiform activity during REM sleep,
unless RBD can be clearly distinguished from any
concurrent REM sleep-related seizure disorder.
D. The sleep disturbance is not better explained by another
sleep disorder, medical or neurologic disorder, mental
disorder, or substance use disorder.
EEG = electro-oculogram; EMG = electromyogram; PSG = polysomnography;
RBD = rapid eye movement sleep behavior disorder; REM = rapid eye
movement.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Pathophysiology of RBD
In animal experiments, lesions in areas of the pons (subcoe-
ruleus in cat, sublateral dorsal nucleus in the rat) can result
in body movements during REM sleep.25 As discussed in
Chapter 24, descending pathways from atonia regions of the
pons result in hyperpolarization and inhibition of spinal
motor neurons (mediated by gamma-aminobutyric acid
[GABA] and glycine) during REM sleep. Damage to the
atonia regions or the descending pathways can result in REM
sleep without atonia. However, the precise anatomic changes
and pathophysiology associated with REM without atonia in
humans remain controversial. Furthermore, REM sleep
without atonia is only one of the manifestations of RBD.
Areas of the brain such as the limbic system are likely involved
in the generation of violent dreams and the associated emo-
tions. Either a disorder or release from inhibition of loco-
motor pattern generators must also be involved in RBD
pathophysiology. The fact that RBD may be a harbinger
of future development of disorders such as Parkinsons
disease24,25,27 has led some to hypothesize that dysfunction of
areas of the brain such as the striatum may be associated with
RBD. One study found reduced striatal dopamine transport-
ers in patients with idiopathic RBD compared with normal
controls.28 Of interest, Parkinsons disease patients had the
most severe reduction in striatal dopamine receptors consis-
tent with the idea that RBD may represent an early manifesta-
tion of Parkinsons disease in a significant number of patients.
Classifications and Causes of RBD
An acute form of RBD can occur after withdrawal from
REM suppressants, such as ethanol. Even after extensive
BOX 2810
Classification and Causes of Rapid Eye Movement
Behavior Disorder
ACUTE RBD
Alcohol withdrawal
Substance abuse or withdrawal (barbiturates)
Medication toxicity (caffeine, MAOIs, TCAs)
CHRONIC RBD
Idiopathic
Associated with other sleep disorders
Narcolepsy
Associated with alpha synucleopathies
Parkinsons disease
Lewy body dementia
Multiple system atrophy
Associated or worsened with medications
SSRIs (fluoxetine, paroxetine)
Venlafaxine
Mirtazapine
TCAs (imipramine)
MAOIs = monoamine oxidase inhibitors; RBD = rapid eye movement sleep
behavior disorder; SSRIs = selective serotonin reuptake inhibitors; TCAs =
tricyclic antidepressants.
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evaluation, about 60% of cases of chronic RBD are idiopathic
(see Box 2810). Causes of chronic RBD include multiple
sclerosis, subarachnoid hemorrhage, dementia, ischemic
cerebrovascular disease, and brainstem neoplasms.2426 RBD
can be associated with a number of neurologic disorders
including narcolepsy and alpha synucleopathies including
Parkinsons disorder, Lewy body dementia, and multiple
system atrophy.24,25 In one study, almost 40% of patients with
idiopathic RBD later developed Parkinsons syndrome,
although the mean time from onset of RBD to onset of Par-
kinsons disease was approximately 12 years.27 There is a strong
male predominance in RBD. The acute onset of RBD in a
middle-aged woman with other neurologic complaints should
raise the possibility of multiple sclerosis. Drug-induced or
drug-exacerbated cases of RBD have been reported (see Box
2810) with the use of monoamine oxidase inhibitors (e.g.,
phenelzine), TCAs (e.g., imipramine), SSRIs (e.g., fluoxetine),
selective serotonin norepinephrine reuptake inhibitors (ven-
lafaxine), and other antidepressants (mirtazapine).26 There
can also be a sudden exacerbation of RBD when the dose of
medications associated with RBD is increased.
Pseudo-RBD A group of patients with a history of dream-
enactment behavior and daytime sleepiness was found to
have OSA on PSG but no evidence of REM sleep without
atonia.29 Treatment with CPAP eliminated the behaviors. It
is possible that increased pressure for REM sleep (prior REM
sleep fragmenation) overwhelms normal REM atonia pro-
cesses in these cases. Of note, patients with both true RBD
and OSA may also exhibit fewer RBD episodes when ade-
quately treated with CPAP.
PSG in RBD Video PSG including both leg and arm EMG is
recommended. A given PSG study may or may not reveal an
episode of abnormal behavior/body movements, because
most patients do not have nightly attacks. For this reason,
some sleep centers perform multiple sleep studies if the diag-
nosis remains unclear. However, even if abnormal behavior
is not documented by a given PSG, evidence of REM sleep
without atonia (tonic or phasic EMG abnormality during
REM sleep) is usually present. The American Academy of
Sleep Medicine (AASM) scoring manual30 provides criteria
for scoring the EMG activity associated with RBD (Box 28
11). In the chin EMG, sustained muscle activity may be
noted. Excessive phasic activity (TMA) may be noted in the
chin EMG, limb EMGs (anterior tibial, extensor digitorum),
or both (see Chapter 12). TMA in the leg EMG derivations
can also be seen without evidence of sustained muscle activ-
ity in the chin EMG (Figs. 283 and 284).
When the chin EMG derivation is abnormal, identifica-
tion of REM sleep (vs. stage W) may be challenging. Epochs
could potentially be scored as stage W (REMs + increased
chin EMG). Clues that abnormal REM sleep is present
include the presence of saw-tooth waves in the EEG, exces-
sive TMA in the chin and/or limb EMGs, and alterations in
airflow associated with bursts of eye movements. The heart
rate also may remain constant despite the sudden appearance
of increased EMG tone (as opposed to an awakening). TMA
Chapter 28 Parasomnias 575
BOX 2811
Scoring Rules for the Electromyogram Activity
Associated with the Rapid Eye Movement Sleep
Behavior Disorder
RULES
1. The PSG findings of RBD are characterized by either or
both of the following features:
a. Sustained muscle activity in REM sleep in the chin
EMG.
b. Excessive transient muscle activity during REM in the
chin or limb EMG.
DEFINITIONS
Sustained muscle activity in REM sleep is defined as an
epoch of REM sleep with at least 50% of the duration of the
epoch having a chin EMG amplitude greater than the
minimum amplitude in NREM.
Excessive transient muscle activity in REM sleep: In a
30-second epoch of REM sleep divided into 10 sequential
3-second miniepochs, at least 5 (50%) of the miniepochs
contain bursts of transient muscle activity. In RBD, excessive
transient muscle activity bursts are 0.1 to 5.0 seconds in
duration and at least four times as high in amplitude as the
background EMG activity.
EMG = electromyogram; NREM = nonrapid eye movement;
PSG = polysomnography; RBD = rapid eye movement sleep behavior
disorder; REM = rapid eye movement.
Adapted from Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American
Academy of Sleep Medicine: The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology and Technical Specification, 1st ed.
Westchester, IL: American Academy of Sleep Medicine, 2007.
can also be mistaken for periodic limb movement in sleep
(PLMS) activity. However, TMA usually contains many more
brief spikes of activity. Of interest, during RBD body move-
ments, video monitoring of the face will often show closed
eyes but obvious movements of the eyes under the eyelids
consistent with REMs. In contrast, during confusional
arousals or sleepwalking, the eyes are typically open with a
blank stare and dilated pupils (affected individual is still
minimally responsive).
Whereas the AASM scoring manual provides criteria to
determine whether a given epoch has sufficient activity in
the chin and limb EMGs during REM sleep to be classified
as abnormal or excessive (see Box 2811), the number of
such epochs (as a percentage of the total amount of REM
sleep) that should be considered to be abnormal was not
specified. In fact, it is really not possible to define what is
abnormal given the night-to-night variability in manifesta-
tions of RBD. Some evidence of REM without atonia can be
seen in patients taking SSRIs who have no history of dream
enactment. As is discussed in the next section, a diagnosis
of RBD requires more than REM sleep without atonia.
Diagnosis of RBD
The ICSD-2 criteria for RBD are listed in Box 289. The
major points are demonstration of REM sleep without
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576 Chapter 28 Parasomnias

100 V
F4-M1
C4-M1
O2-M1
E1-M2
E2-M2
Chin
ECG
Snore
CPAP flow

Chest

Abdomen

SpO2

RAT
LAT

FIGURE 283 A 30-second epoch of rapid eye movement (REM) sleep shows both sustained and phasic chin electromyogram (EMG) activity during REM sleep (REM sleep without
atonia) and increased transient muscle activity (phasic) in the right anterior tibial (RAT) and left anterior tibial (LAT) EMG derivations. CPAP = continuous positive airway pressure;
ECG = electrocardiogram; SpO2 = pulse oximetry.

Moving arms and legs and talking

100 V
F4-M1
C4-M1
O2-M1
E1-M2

E2-M2

Chin
ECG

RAT
LAT
A B C

FIGURE 284 A 30-second epoch during stage R (REM) sleep. At A, the chin EMG is not increased but transient muscle activity is noted in the leg EMG derivations. At B, the chin
shows sustained and increased phasic EMG activity but there is no increased EMG activity in the legs. At C, both chin and leg EMG activity is increased. At B and C, the patient was
moving arms and legs and talking. ECG = electrocardiogram; LAT = left anterior EMG; RAT = right anterior tibial EMG.

atonia (sustained chin EMG activity) or increased TMA
during REM sleep (chin, limbs, or both), abnormal dream-
enacting behavior documented by history or video PSG,
and absence of epileptiform activity during REM sleep
(unless RBD can be clearly distinguished from any concur-
rent REM sleep-related seizure disorder). Seizure disor-
ders can present with manifestations virtually identical
to those of RBD. Therefore, making a diagnosis of RBD
without PSG monitoring is not recommended. Absence of
REM without atonia and/or body movements out of NREM
sleep would be inconsistent with RBD. Nocturnal epilepsy
occurs most commonly out of NREM sleep but can rarely
occur out of REM sleep (NREM > wake > REM). A
detailed neurologic evaluation of patients suspected of
having RBD is indicated with attention to symptoms and
signs of associated neurologic disorders such as Parkinsons
disease (see Box 2810). A magnetic resonance imaging
(MRI) study of the brain (to rule out structural causes) and
a full clinical EEG (preferably during sleep) are usually
performed especially if manifestations are atypical or
patients do not respond to therapy. Important facts about
RBD are listed in Box 2812.
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BOX 2812
Rapid Eye Movement Sleep Behavior
Disorder Facts
Male predominance (8090%)
Older age (usually presents after 50 yr, but can occur in
younger patients)
Sleep-related injury common
Dream enactment
Altered dream process and contentviolent and
combative
Tonic and phasic (transient muscle activity) chin EMG
activity and phasic limb EMG activity during REM sleep
Preserved sleep architecture (normal amount of REM
sleep, stage N3 can be increased)
Periodic limb movements during NREM sleep
Efficacy of clonazepam treatment (>80%)
EMG = electromyogram; NREM = nonrapid eye movement; REM = rapid eye
movement.
Adapted from Schenck CH, Mahowald MW: REM sleep behavior disorder:
clinical, developmental, and neuroscience perspective 16 years after its
formal identification in sleep. Sleep 2002;25:120138.
Variants of RBD
REM Sleep without Atonia This variant includes findings of
REM sleep without atonia without a clinical history of RBD.31
There can be limb twitching without overt body movements.
This is common in patients taking SSRIs. There is some evi-
dence that some of these patients go on to develop RBD.
Parasomnia Overlap Disorder Parasomnia overlap disorder
consists of a combination of RBD and NREM parasomnias
(sleepwalking, confusional arousals, sleep terrors).32 Diag-
nostic criteria for both RBD and one or more of the NREM
parasomnias must be met. Most patients with overlap para-
somnia had some manifestation of an NREM parasomnia in
childhood. Overlap parasomnia can be idiopathic or associ-
ated with narcolepsy, multiple sclerosis, brain tumor, and
psychiatric disorders. The disorder may respond to treat-
ments used for RBD such as clonazepam.
Status Dissociatus The ICSD-2 states that SD can be consid-
ered a subtype of RBD. SD is characterized by state dissocia-
tion without identifiable sleep stages but with sleep and
dream-related behaviors that resemble RBD.33 SD represents
a breakdown of the typical markers of wake, NREM, and
REM sleep. The patient may think she or he is awake but
others think she or he is asleep. An underlying medical or
neurologic condition, including narcolepsy, Parkinsons
disease, dementia with Lewy bodies, and multiple system
atrophy, is nearly always present. Of special interest, fatal
familial insomnia and advanced human immunodeficiency
virus (HIV) can manifest SD.
Useful factors differentiating SD from RBD or the overlap
parasomnias are that the sleep stage before SD behavior is
not discernible (parasomnia does not occur out of NREM or
REM sleep) and the patient when awakened does not realize
Chapter 28 Parasomnias 577
BOX 2813
Treatments for Rapid Eye Movement Sleep
Behavior Disorder
Environmental precautions
Clonazepam
Melatonin
Other less frequently used medications
Nonclonazepam BZRAs (temazepam, triazolam,
alprazolam)
Dopamine agonists (pramipexole)
Carbamazepine
BZRAs = benzodiazepine receptor agonists.
that he or she has been sleeping. That is, the behavior occurs
out of a state not clearly awake or asleep.
Differential Diagnosis of RBD
The differential diagnosis of RBD includes sleep-related
seizure activity, sleep-related dissociative disorders, PLMS,
sleepwalking, sleep terrors, confusional arousals, nocturnal
panic attacks, nightmares, and the PTSD. In contrast to
RBD, sleepwalking (and variants) classically occurs during
slow wave sleep (stage N3) and, hence, is most common in
the early portion of the night. Unlike RBD, the majority of
adults with sleepwalking had episodes during childhood.
When patients are awakened during sleepwalking or sleep
terror episodes, they are quite confused and tend to have no
memory of dream content. If content is remembered, usually
it is not as complex as a typical dream. However, recent
studies of sleepwalking and sleep terrors in adults have
shown that episodes can begin in stage N2 sleep and during
the second part of the night.6 In addition, the separation
between sleepwalking/sleep terrors and RBD is not
absolutesome patients have violent behavioral episodes
occurring in both NREM and REM sleep (parasomnia
overlap disorder). Both nightmares and the PTSD can be
associated with violent or terrifying dream content and
arousal from sleep.34 However, complex body movements are
uncommon with these disorders. In addition, nocturnal
seizure activity usually occurs in NREM sleep, and behaviors
typically are more stereotyped and less complex than in
RBD. However, cases of a seizure disorder presenting with
sleepwalking and/or injurious behavior that mimics RBD
have been reported.6
Treatment of RBD
There have been no randomized, controlled clinical trials for
treatment of RBD. Evidence for treatment comes from case
series or anecdotal case reports.2831 Treatment options are
listed in Box 2813. A best clinical practice guide to treat-
ment of RBD developed by the Standards of Practice Com-
mittee of the American Academy of Sleep Medicine35 has
recently been published following a systematic review of the
published literature. Environmental precautions are an
essential first step in RBD treatment because, even with
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effective treatment with medications, breakthrough episodes
do occur. Environmental precautions include having the
bedmate sleep in a separate room or bed, closed and locked
windows and doors, removal of furniture with sharp edges,
and use of mattress or pads on the floor near the bed.
The most evidence for effective RBD treatment is for use
of clonazepam. Successful treatment of RBD has been
achieved with clonazepam 0.5 to 2 mg (4 mg) given 30
minutes before bedtime in approximately 80% to 90% of
patients. Clonazepam dramatically reduces episode fre-
quency or severity but usually does not totally eliminate
the findings of REM sleep without atonia. The medication
also does not work by decreasing the amount of REM sleep.
Clonazepam may modify dream content or inhibit the brain-
stem locomotor pattern generators. Clonazepam has a half-
life of 30 to 40 hours and can cause early morning sedation,
confusion, motor incoordination, or memory dysfunc-
tion.35,36 It may also increase risk of falls or worsen OSA. A
response hierarchy with increasing doses has been described
with the following sequentially decreasing with dose escala-
tion: vigorous violent behavior > complex nonvigorous
behavior > simple limb jerking > excessive EMG twitching
in stage R. Unfortunately, a significant proportion of RBD
patients treated with clonazepam have one or more signifi-
cant side effects.36
Melatonin in doses of 3 to 12 mg has also been found
to be effective treatment for RBD either as a sole agent or
as an add on to clonazepam.37 Side effects of melatonin
include hallucinations, morning headaches, nightmares, and
morning sleepiness. In contrast to clonazepam, some studies
suggest that melatonin decreases the number of stage R
epochs without atonia.
Successful treatment of RBD has also been reported (case
reports with small patient numbers) with pramipexole (total
dose 0.751.5 mg),38 paroxetine, acetylcholinesterase inhibi-
tors, BZRAs other than clonazepam (temazepam, triazolam,
alprazolam), clozapine, Yi-Gan San (an herbal medication),
and carbamazepine.39 If episodes of what appears to be RBD
do NOT respond to clonazepam but DO respond to an anti-
epileptic medication such as carbamazepine, this is a clue
that a seizure disorder rather than RBD may actually be
present.
Recurrent Isolated Sleep Paralysis
Recurrent isolated sleep paralysis is characterized by inabil-
ity to move at sleep onset (hypnagogic) or on awakening
(hypnopompic) (Box 2814).1 Patients are awake and have
full recall for the event. Although diaphragmatic function is
not affected, a sensation of dyspnea is common. Episodes can
be aborted by the affected individual being touched or
spoken to or by making intense efforts to move. The term
isolated refers to the fact that other sleep disorders such as
narcolepsy or idiopathic hypersomnia are not present. The
frequency of sleep paralysis episodes is very variableonce
per lifetime to several per month. Hallucinatory experiences
accompany sleep paralysis in 25% to 75% of individuals.
BOX 2814
Recurrent Isolated Sleep Paralysis
Diagnostic Criteria
A. The patient complains of inability to move the trunk and
all limbs at sleep onset or on awakening from sleep.
B. Each episode lasts seconds to a few minutes.
C. The sleep disturbance is not better explained by another
sleep disorder (particularly narcolepsy), a medical or
neurologic disorder, mental disorder, medication use, or
substance use disorder.
Note: Hallucinatory experiences may be present but are not
necessary.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Epidemiology of Sleep Paralysis
Studies of students suggest 15% to 40% experience at least
one episode of sleep paralysis. Sleep paralysis is also common
in patients with narcolepsy and idiopathic hypersomnia.
Precipitating Events
Sleep disruption, irregular sleep periods, sleep deprivation,
and stress are known triggers.40
Diagnosis of Recurrent Sleep Paralysis
The ICSD-2 diagnostic criteria are listed in Box 2814. Note
the requirement that the presence of sleep paralysis must
not be better explained by another sleep disorder (especially
narcolepsy). Sleep paralysis would not be classified as iso-
lated if associated with another sleep disorder such as
narcolepsy.
Differential Diagnosis of Recurrent Sleep Paralysis
The differential diagnosis of sleep paralysis includes familial
periodic paralysis syndromes, atonic seizures, cataplexy, and
nocturnal panic attacks. Episodes of familial periodic paraly-
sis (especially hypokalemic period paralysis) last for hours,
may be associated with carbohydrate intake, and in the
hypokalemic variant, are associated with hypokalemia.1
In contrast, sleep paralysis is associated with sleep-wake
transitions.
Treatment of Sleep Paralysis
In most cases, treatment with medications is not needed.
Avoiding sleep deprivation and following a regular sleep
pattern may help prevent isolated sleep paralysis: Serotonin
reuptake inhibitors (in antidepressant doses) and TCAs (low
doses) are usually effective treatment for isolated sleep paral-
ysis. None of these are U.S. Food and Drug Administration
(FDA) approved for this indication.
Nightmare Disorder
Nightmare disorder (dream anxiety attacks) are character-
ized by recurrent nightmares, which are disturbing mental
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BOX 2815
Nightmare DisorderDiagnostic Criteria
A. Recurrent episodes of awakenings from sleep with recall
of intensely disturbing dream mentation, usually
involving fear or anxiety, but also anger, sadness,
disgust, and other dysphoric emotions.
B. Full alertness or awakening, with little confusion or
disorientation; recall of sleep mentation is immediate
and clear.
C. At least one of the following associated features is present:
i. Delayed return to sleep after the episode.
ii. Occurrence of episodes in the latter half of the
habitual sleep period.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
BOX 2816
Medications Commonly Associated
with Nightmares
Beta blockerspropranolol, atenolol
Cholinergic agonistsdonepezil
Antibioticslevaquin
Antiviral agentsamantadine, gancyclovir
Antiretroviralefavirenz (Sustiva)
Dopamine agonistsropinirole, pramipexole
Antidepressantsfluoxetine, paroxetine
Benzodiazepine receptor agonists (zolpidem)
Melatonin agonistramelteon
Ethanol withdrawalREM rebound
REM = rapid eye movement.
experiences that usually occur during REM sleep and often
result in an awakening (Box 2815). Nightmares can follow
acute trauma (acute stress disorder [ASD]) or occur 1 month
or more after trauma (PTSD). The dreams of PTSD can
occur out of NREM stages N2 or N3, during REM sleep, and
at sleep onset. A number of medications can also be associ-
ated with nightmares41 (Box 2816).
Epidemiology of Nightmare Disorder
Fifty percent to 80% of adults report one or more night-
mares.1 Ten percent to 50% of children age 3 to 5 experience
nightmares severe enough to disturb their parents. Night-
mares within 3 months of trauma are present in up to 80%
patients with PTSD.1
PSG Recordings in Nightmare Disorder
Few PSG studies of nightmares exist, but typically, acceler-
ated heart rate and respiratory rate precede awakening from
REM sleep with report of a nightmare.
Diagnosis of Nightmare Disorder
The ICSD-2 diagnostic criteria for the nightmare disorder
are listed in Box 2815. Note that recurrent episodes
Chapter 28 Parasomnias 579
are required. One would probably not classify the rare
occurrence of a nightmare as a disorder given the high per-
centage of normal individuals experiencing an occasional
nightmare.
Differential Diagnosis
The differential diagnosis of nightmare disorder includes
sleep terrors, RBD, sleep paralysis, SRDDs (to be discussed
in a later section), and nocturnal panic attacks. Nocturnal
panic attacks occur during or immediately after nocturnal
awakenings from NREM sleep. Some patients report that
disturbing dreams preceded the attacks but most do not have
dream recall.
Treatment of Nightmare Disorder
If a medication is temporally associated with nightmares, a
trial of medication discontinuation or change is prudent.
Cognitive behavioral treatments have been used to treat
nightmares with some success. One behavioral technique
called imagery rehearsal therapy has proved successful in
several studies.42,43 Patients are asked to rewrite their previ-
ous dreams with a positive outcome. In the past, use of
medications for nightmares had limited success. Recently,
several small studies report success with the alpha 1 blocker
prazosin. Note that when prazosin is started, the drug
should be initiated with a dose of 1 mg at bedtime to avoid
severe first-dose hypotension (often orthostatic hypoten-
sion). The drug can then be titrated upward slowly over
several nights. A parallel placebo-controlled study in trau-
matic nightmares in PTSD associated with combat showed
improvements in sleep and reduction in nightmares. A rela-
tively high dose (mean 13 mg) was reached over a protracted
period of upward titration.44 Another study using a cross-
over design and a dose of 2 to 6 mg at bedtime also found
benefit in civilian trauma PTSD.45 One study also reported
success in reducing disturbing nightmares using topiramate
in PTSD patients.46 However, neither prazosin or topiramate
are FDA approved for treatment of nightmares in PTSD.
Prazosin must be used with caution to avoid hypotension.
OTHER PARASOMNIAS
Sleep-Related Dissociative Disorders
The ICSD-21 states sleep-related dissociative disorders
(SRDD) emerge throughout the sleep period during well-
established EEG wakefulness, either at transition from
wakefulness to sleep or within several minutes after awaken-
ing from stage N1, N2, or R (Box 2817). An important
distinction from other parasomnias is that whereas typi-
cal parasomnias tend to emerge almost simultaneously
with arousal, the SRDDs emerge from well-established
wakefulness.
The Diagnostic and Statistical Manual of Mental Disor-
ders, 4th edition (DSM-IV), states that a dissociative disor-
der is characterized by a disruption in the usually integrated
functions of consciousness, memory, identity, or perception
of the environment.47 An SRDD would include dissociative
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580 Chapter 28 Parasomnias
BOX 2817
Sleep-Related Dissociative Disorders
Diagnostic Criteria
A. A dissociative disorder must fulfill Diagnostic and
Statistical Manual of Mental Disorders, 4th ed. (DSM-IV),
criteria and emerges in close association with the
main sleep period.
B. One of the following is present:
i. PSG demonstrates a dissociative episode or episodes
that emerge during sustained EEG wakefulness, either
in the transition from wakefulness to sleep or after an
awakening from NREM or REM sleep.
ii. In the absence of a PSG-recorded episode of
dissociation, the history provided by observers is
compelling for a sleep-related dissociative disorder,
particularly if the sleep-related behaviors are similar
to observed daytime dissociative behaviors.
C. The sleep disturbance is not better explained by another
sleep disorder, a medical or neurologic disorder, mental
disorder, medication use, or substance use disorder.
EEG = electroencephalogram; NREM = nonrapid eye movement;
PSG = polysomnography; REM = rapid eye movement.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
behavior that occurred out of wakefulness during the sleep
period in which there was an impairment of identity,
memory, or state of consciousness.
Types of Dissociative Disorders Associated with Sleep
There are five diagnostic categories of DDs in DSM-IV47
including (1) dissociative identity disorder (formerly multi-
ple personality disorder), (2) dissociative fugue, (3) disso-
ciative amnesia, (4) depersonalization disorder, and (5)
dissociative disorder not otherwise specified (DD NOS). Of
these, three are considered SRDD: dissociative identity dis-
order, dissociative fugue, and DD NOS. Most but not all
patients with SRDD have both daytime DD episodes as well
as previous episodes of SRDD.1,48
Dissociative Identity Disorder In dissociative identity disorder,
a person displays multiple identities and personalities each
with its own pattern of perceiving and integrating with the
environment. A minimum of two personalities is required.
Dissociative Fugue State The dissociative fugue state is charac-
terized by reversible amnesia for personal identity and mem-
ories usually lasting hours to days. A dissociative fugue state
usually involves unplanned travel or wandering and is some-
times associated with establishment of a new identity. After
the episode, prior memories return but there is amnesia for
the fugue episode.
Dissociative Disorder Not Otherwise Specified The classification
DD NOS is used for a DD that does not fit the criteria for a
specific DD.
BOX 2818
Sleep-Related Dissociative Disorders Facts
SRDDs occur out of established wakefulness.
Most patients have daytime DD.
There is a female predominance.
Most patients have a history of physical or sexual trauma/
abuse.
DD = dissociative disorder; SRDD = sleep-related dissociative disorder.
BOX 2819
Sleep EnuresisDiagnostic Criteria
PRIMARY SLEEP ENURESIS
A. The patient is older than 5 years.
B. The patient exhibits recurrent involuntary voiding
during sleep, occurring at least twice a week.
C. The patient has never been consistently dry during
sleep.
SECONDARY SLEEP ENURESIS
A. The patient is older than 5 years.
B. The patient exhibits recurrent involuntary voiding
during sleep, occurring at least twice a week.
C. The patient has been previously consistently dry
during sleep for at least 6 months.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Epidemiology SRDD are more common in females.1 In
patients with SRDD, the age of onset is usually from child-
hood to middle adulthood. In one study of 100 consecutive
patients referred to a sleep disorders clinic, 7% were diag-
nosed with SRDDs.6 The majority of patients with SRDDs
have a history of physical or sexual trauma/abuse.
Diagnosis of SRDD The ICSD-2 diagnostic criteria are listed
in Box 2817 and important facts are displayed in Box
2818.
Treatment of SRDDs The treatment of SRDD involves the treat-
ment of the underling DD. Psychotherapy is the main treat-
ment for DD with the goal of encouraging communication
of conflicts and increased insight. The overall goal is to help
the individual come to terms with the stress or trauma that
triggered the DD.
Sleep Enuresis
Sleep enuresis is characterized by involuntary voiding during
sleep. Sleep enuresis is divided into primary sleep enuresis
and secondary sleep enuresis (Box 2819).49 In primary
enuresis, the patient has never been consistently dry after
age 5 years. In secondary enuresis, the patient was previously
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BOX 2820
Causes of Secondary Enuresis
1. Inability to concentrate urine (DI, nephrogenic DI, sickle
cell anemia).
2. Increased urine production (caffeine, medications).
3. Urinary tract pathologyUTI, malformations of urinary
tract.
4. Chronic constipation and encopresis (bulging colon
constricts bladder capacity).
5. Neurologic disorders: seizures, neurogenic bladder.
6. OSA.
7. Psychosocial stress: parental divorce, neglect, physical or
sexual abuse.
DI = diabetes insipidus; OSA = obstructive sleep apnea; UTI = urinary tract
infection.
consistently dry. The classification is useful because each
group has characteristic causes.
Primary Enuresis
The patient either fails to arouse from sleep when the bladder
is full or fails to inhibit a bladder contraction. These are both
acquired skills and are developed at different ages in different
individuals. A limit of age 5 years is somewhat arbitrary. The
spontaneous cure rate for enuresis after age 5 is approxi-
mately 15%/year. Some children with primary enuresis have
absence of the nocturnal secretion of vasopressin (antidi-
uretic hormone). In primary enuresis, the ratio of males
to females is 3 : 2. Hereditary factors are important in
primary enuresis. The risk of sleep-related enuresis is 77% if
both parents had enuresis and 44% when one parent had
enuresis.
Secondary Enuresis
Secondary enuresis has a number of causes (Box 2820).
Evaluation commonly involves history (for snoring and signs
of sleep apnea) and a urinalysis (looking for infection, dia-
betes, and other evidence of renal disease). Ultrasonography
of the pelvis is recommended, especially in children with
daytime symptoms. Nocturia or frequent urination suggests
small bladder capacity. Daytime incontinence or failure to
respond to treatment is an indication for referral to a special-
ist. Physical examination should check for neurologic
impairment and stigmata of spinal cord abnormality. The
anal wink should also be assessed. Palpation of the abdomen
may show retained stool, which can compress the bladder
and reduce capacity.
PSG in Evaluation of Enuresis
A sleep study is indicated if OSA or nocturnal seizures are
suspected. Untreated OSA in children can worsen or cause
enuresis.4951 Therefore, sleep apnea should be considered
in all children being evaluated for enuresis, especially sec-
ondary enuresis. Episodes of enuresis can occur in all sleep
stages, during nocturnal wakefulness, and in association
with transient arousals.
Chapter 28 Parasomnias 581
BOX 2821
Treatments for Sleep-Related Enuresis
Behavioral treatments (frequent daytime voiding, fluid
restriction at night).
Alarm treatments (wet bed triggers alarm).
Evaluation for sleep apnea and genitourinary pathology if
indicated.
Drug therapy: vasopressin, anticholinergics (oxybutynin),
tricyclic antidepressants.
Treatments for Enuresis
Treatments for enuresis are listed in Box 2821. These
include behavioral techniques to encourage regular voiding
during the day, alarm treatments (alarm sounds when bed-
wetting is detected), evaluation for genitourinary malforma-
tions, and drug therapy (e.g., vasopressin, anticholinergics,
TCAs).49 The medications that are used are treatments and
not cures. Relapse will occur if medication is suddenly dis-
continued. Oral vasopressins (fast-melting formulations
120360 g before bedtime) reduce urine volume. The nasal
spray formulations have a longer duration of action and are
no longer recommended (more risk for hyponatremia). With
vasopressin, the major concern is hyponatremia, which can
be avoided by fluid restriction after dinner. The anticholin-
ergic oxybutynin, tablets or syrup, before bedtime relaxes the
bladder. A combination of vasopressin and oxybutynin has
also been used. TCAs (imipramine 2550 mg before
bedtime) are effective but the mechanism is unclear. Because
of substantial side effects, TCAs are third-line treatment.
Sleep-Related GroaningCatathrenia
Sleep-related groaning (catathrenia) is a chronic (often
nightly) disorder characterized by expiratory groaning, most
often out of REM sleep (especially in the REM episodes in
the second part of the night). Catathrenia can also occur
in NREM sleep. It may be associated with bradypneic
episodes (slow respiratory rate) with long exhalations. Typi-
cally, a large inspiration is followed by a protracted expira-
tion during which a monotonous vocalization (mournful
moaning or groaning) is produced (Fig. 285). The catathre-
nia events tend to occur in clusters and are often associated
with bradycardia. Patients are usually unaware of the groan-
ing. The disorder is thought to be benign and its main com-
plication is disturbance of the bed partner.5255
Epidemiology
Catathrenia is very rare, with onset usually in adolescence or
early adulthood (mean age 19 yr with a range of 536 yr).1
The prevalence of catathrenia is greater in men than in
women.
Polysomnography
Catathrenia events usually occur in the second part of the
night and may occur in clusters resembling a run of central
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582 Chapter 28 Parasomnias

LOC

ROC

Fz-Cz

Cz-Oz

C4-A1

Arousal at the end of

Chin EMG exhalation

Arm EMG

ECG

Nasal P

SpO2

Sum (A)
Inspiration

RC
(B)

Abd

HR

FIGURE 285 A 120-second tracing during REM sleep shows a deep inhalation (A) followed by a prolonged exhalation (B) associated with monotonous sound generation
(groaning). Note that in the Sum, rib cage (RC), and abdominal (Abd) tracings, the direction of inspiration is downward and exhalation upward. The absence of nasal pressure
excursions is due to exhalation through the mouth during groaning. ECG = electrocardiogram; EMG = electromyogram; HR = heart rate; LOC = left outer canthus; Nasal P = nasal
pressure; ROC = right outer canthus; SpO2 = pulse oximetry. Reproduced from Ramar K, Olson EJ, Morgenthaler TI: Catathrenia. Sleep Med 2008;9:457459.

apneas. An EEG arousal with or without body movement BOX 2822

often marks the end of the event. Sleep-Related Groaning (Catathrenia)
Diagnostic Criteria
Diagnosis of Catathrenia
A. History of regularly occurring groaning (or related
The ICSD-2 criteria for catatherenia are listed in Box 2822.
monotonous vocalization) occurring during sleep.
Diagnosis can be based on history or PSG. Clusters of
catathrenia events can be confused with central apneas. OR
However, in central apneas, an exhalation precedes the long B. PSG with respiratory sound monitoring reveals
inspiratory pause. In contrast, in catathrenia, a deep inspira- characteristic respiratory dysrhythmia predominantly or
tion precedes the long expiratory pause (see Fig. 285). Mild exclusively during REM sleep.
bradycardia during the exhalation is common. PSG = polysomnography; REM = rapid eye movement.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Differential Diagnosis of Catathrenia Westchester, IL: American Academy of Sleep Medicine, 2005.
The differential diagnosis of catathrenia includes stridor,
sleep-related laryngospasm, and sleep talking. Stridor can be
inspiratory or expiratory, occurs with every breath, and does
not have a prolonged expiratory phase. Sleep-related laryn-
gospasm is associated with a sense of suffocation. Sleep
talking consists of words rather than groans.
DaneshGroup.com

Treatment of Catathrenia
Not all cases require treatment. Multiple medications have
been tried without success. There are two case reports of a
benefit from CPAP treatment,56,57 whereas another study did
not find a benefit from CPAP.54
Exploding Head Syndrome
The exploding head syndrome (EHS) is characterized by a
sudden loud imagined noise or sense of violent explosion in
the head occurring as the patient is falling asleep on waking
during the night.1,58 The event can be described as a painless
loud bang, a clash of cymbals, or a bomb exploding.
Epidemiology
The median age of onset is 58 years, but it can occur at
any age.1
Diagnosis
The ICSD-2 diagnostic criteria for the exploding head syn-
drome are listed in Box 2823. Note that pain is absent and
the patient typically arouses with a sense of fright.
Demographics
The prevalence is not known; however, the EHS is more
common in women than in men. Onset at all ages has been
reported.
Polysomnography
Limited data suggest the exploding head events occur during
drowsiness while the subject is still awake.
Differential Diagnosis of Sleep-Related Headaches
A number of sleep-related headaches exist.1,5961 For detailed
information on diagnostic criteria for different headache
syndromes, the reader can review the International Classifi-
cation of Headache Disorders, 2nd edition,61 published by
the International Headache Society:
1. Idiopathic stabbing headache (icepick headache)
sudden jabbing pain on the side of head.
BOX 2823
Exploding Head SyndromeDiagnostic Criteria
A. The patient complains of a sudden loud noise or sense
of explosion in the head either at the wake-sleep
transition or upon waking during the night.
B. The experience is NOT associated with significant pain
complaints.
C. The patient rouses immediately after the event, usually
with a sense of fright.
Note: In a minority of cases, a flash of light or myoclonic
jerk may accompany the event.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Chapter 28 Parasomnias 583
2. Thunderclap headachea severe headache associated
with subarachnoid hemorrhage or other causes. It usually
does not occur at sleep onset.
3. Sleep-related migrainesunilateral throbbing often asso-
ciated with photophobia and nausea.
4. Cluster headachesunilateral headaches with retroperi-
orbital pain lasting 15 minutes to 3 hours. The clusters of
headaches last 1 week to 1 year separated by pain-free
periods.
5. Nocturnal paroxysmal hemicraniaunilateral headache
on one side of the face near the eye, often with swollen
eyelid and nasal congestion. It responds to indomethacin.
The headaches may occur multiple times during the day.
6. Simple partial seizuresusually not at sleep onset.
7. Sleep starts (hypnic jerks)motor phenomenon with
sudden myoclonic jerks.
8. Hypnic headachesa rare disorder during which the
headache awakens the patient with two of the following
characteristics: (1) occurs more than 15 times monthly,
(2) lasts longer than 15 minutes after awakening, and (3)
occurs after age 50.60,61 In addition, there should be no
autonomic symptoms and no more than one of the fol-
lowing: nausea, photophobia, and phonophobia. Hypnic
headaches commonly awaken patients 4 to 6 hours after
sleep onset.
Treatment of Exploding Head Syndrome
Only a few case reports of treatment of the exploding head
syndrome have been published. Flunarizine (a calcium
channel blocker not available in the United States),62 nifedip-
ine,63 and clomipramine58 have been effective in individual
cases.
Sleep-Related Hallucinations
Sleep-related hallucinations (SRHs) include hypnagogic
hallucinations (HGHs) at sleep onset, hypnopompic hal-
lucinations (HPHs) on awakening from sleep, and complex
nocturnal visual hallucinations (CNVHs).1 SRHs are pri-
marily visual hallucinatory experiences that occur at sleep
onset or on awakening. However, they may include auditory,
tactile, or kinetic phenomena (sensation of motion or
falling). SRHs may be difficult to differentiate from sleep-
onset or sleep-termination dreaming.
CNVHs are a variant of SRHs in which hallucinations
occur after full awakening from sleep (in wakefulness after
arousal from sleep).1,64 Usually, the affected individual does
NOT remember a specific dream. The hallucinations are
complex vivid visual images (multicolor), usually of people
or animals, that are relatively immobile and may be dis-
torted. Although patients realize that they are awake, the
hallucinations can be very frightening. CNVHs can occur in
patients taking beta blocker medication and those with neu-
rologic degenerative disorders such as Lewy body dementia.
However, CNVHs can occur in neurologically intact indi-
viduals. Of interest, in one description of CNVHs, many of
the patients also had other parasomnias.64
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584 Chapter 28 Parasomnias
Epidemiology
HGH events have a prevalence of 25% to 35% and HPH
events have a prevalence of 7% to 13%. Both HGHs and
HPHs are more common in younger patients. SRHs can
occur in association with sleep paralysis.
Factors Precipitating SRH
Precipitating factors include current drug use, mood disor-
der, anxiety, and past alcohol use.
Associations with SRHs
1. HGHs and HPHs are common, can occur in normal sub-
jects, and are common in patients with narcolepsy or
idiopathic hypersomnia.
2. CNVHs are rare and can occur in idiopathic form. There
may be an association with a neurologic disorder: narco-
lepsy, Parkinsons disease, dementia with Lewy bodies,
visual loss (Charles Bonnet hallucinations), midbrain and
diencephalic pathology (peduncular hallucinosis), and
the use of beta blocker medications.
PSG in SRHs
Little PSG data are available, but HGHs likely represent
sleep-onset REM periods whereas HPHs occur at arousal
out of REM sleep. CNVH events have also occurred out of
NREM sleep.
Diagnosis of SRHs
The ICSD-2 diagnostic criteria for SRHs are listed in Box
2824.
Treatment
No significant information on treatment of CNVHs exists. If
due to beta blocker medications, these should be withdrawn.
One approach could be REM suppressants such as SSRIs or
TCAs. These medications are effective in HPHs or HGHs in
patients with narcolepsy.
BOX 2824
Sleep Related HallucinationsDiagnostic Criteria
A. The patient experiences hallucinations just prior to sleep
onset (hypnagogic) or on awakening during the night or
in the morning (hypnopompic).
B. Hallucinations are primarily visual.
C. The disturbance is not better explained by another sleep
disorder, medical or neurologic disorder, mental
disorder, medication use, or substance use disorder.
Note: Hypnogogic or hypnopompic hallucinations may be
difficult to differentiate from sleep-onset or sleep-
termination dreaming. Complex nocturnal visual
hallucinations may clearly occur in wakefulness following
arousal from sleep.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
Sleep-Related Eating Disorders
Sleep-related eating disorders (SREDs) are manifested by
eating and drinking during the main sleep period (Boxes
2825 and 2826). The behavior must be associated with one
or more of several manifestations including eating peculiar
food items, associated with insomnia due to sleep distur-
bance from the eating episodes, sleep-related injury, danger-
ous behaviors in pursuit of food, morning anorexia, or
adverse consequences of binge eating. In the past, SRED was
differentiated from nocturnal eating syndrome (NES) by the
level of alertness during the episodes and the degree of
recall.1,4,6567 However, there is considerable overlap between
SRED and NES. In the current ICSD-2 diagnostic criteria for
SRED, altered awareness and lack of recall are NOT required.1
In SRED, the degree of alertness and recall for the
eating behavior are variable. Some patients cannot be
brought to full consciousness during the eating events and
BOX 2825
Sleep-Related Eating Disorder
Diagnostic Criteria
A. Recurrent episodes of involuntary eating and drinking
occur during the main sleep period.
B. One or more of the following must be present with the
recurrent episodes of involuntatry eating and
drinking:
i. Consumption of peculiar forms or combinations of
food or inedible or toxic substance.
ii. Insomnia related to sleep disruption from repeated
episodes of eating, with a complaint of
nonrestorative sleep, daytime fatigue, or
somnolence.
iii. Sleep-related injury.
iv. Dangerous behaviors performed while in the
pursuit of food or while cooking food.
v. Morning anorexia.
vi. Adverse health consequence for current binge of
high-calorie foods.
C. The disturbance is not better explained by another sleep
disorder, medical or neurologic disorder, mental
disorder, medication use, or substance use disorder.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
BOX 2826
Sleep-Related Eating Disorder Facts
Strong female predominance
Variable awareness/alertness during episodes
Eating unusual foods (e.g., raw, frozen, toxic)
Variable recall (partial amnesia)
Co-morbid with other sleep disorders and eating disorders
Topiramate, pramipexole, and sertraline are possible
treatments
DaneshGroup.com

have no recall of the event. Others are relatively alert during
the episode and have considerable recall of the event the next
morning. The amount of alertness can even vary between
episodes on a given night. A sensation of hunger is usually
missing and patients may eat in an out of control manner.1
Patients often eat peculiar, nonedible, or even dangerous
substances. These may include frozen food, coffee grounds,
and cat food. Of interest, alcoholic beverages are rarely con-
sumed. High-calorie foods are often chosen. There may be
multiple episodes of eating during a single night.
Demographics
SRED is much more common in females than in males.
Females make up 66% to 83% of affected individuals in
most series. The prevalence is higher in patients with other
eating disorders. Typical age of onset of SRED is 20 to 30
years.
Pathophysiology
The cause of SRED is unknown but more than 50% of
patients have another parasomnia and the strong female
predominance is typical of eating disorders.
Causes of SRED and Association with Other
Sleep Disorders
The causes and associations of SRED are listed in Box 2827.
An idiopathic form does exist when no obvious cause or
association is identified. SRED is most commonly associated
with sleepwalking but can occur with PLMD, restless leg
syndrome, OSA, and circadian rhythm disorders (irregular
sleep phase). Medication-induced SRED has been reported
with BZRAs,66,67 including zolpidem and triazolam, and psy-
chotropic medications (lithium). Zolpidem is by far the
medication most commonly associated with the SRED.
Zolpidem-associated SRED is especially common if patients
take higher than the recommended dose (e.g., zolpidem
20 mg). Patients also report triggering of episodes by stress,
BOX 2827
Causes of Sleep-Related Eating Disorder
1. Idiopathicless common than #2
2. Associated with another sleep disorder
a. Sleepwalkingmost common association
b. Obstructive sleep apnea
c. PLMD, RLS
d. Circadian rhythm sleep disorders (esp. irregular
sleep-wake type)
3. Associated with medication
a. BZRAs: zolpidem, triazolam
b. Psychotropic medications (lithium, olanzapine,
risperidone)
c. Anticholinergic medications
BZRAs = benzodiazepine receptor agonists; PLMD = periodic limb movement
disorder; RLS = restless legs syndrome.
Chapter 28 Parasomnias 585
cigarette smoking cessation, and cessation of alcohol or other
drugs of abuse.1,66
PSG in SRED
PSG may show multiple arousals from stage N3 with behav-
ior typical of confusional arousal (with or without attempted
eating behavior). Sometimes, OSA or PLMS is also noted.
SRED Complications
Complications include weight gain or injury due to prepara-
tion of food (cookinge.g., burns, opening cans, cutting
food with a knife).
Diagnosis
The ICSD-2 diagnostic criteria are listed in Box 2825.
Observations by a significant other, finding evidence of noc-
turnal eating behavior (e.g., open food packages, dirty
plates), videotaping, and self-report (in patients with some
recall) have been used to make a diagnosis.
Differential Diagnosis
Other possible etiologies of this behavior include NES, recur-
rent hypersomnia (Kleine-Levin syndromehyperphagia,
hypersomnia). Whereas NES is said to be characterized by
full alertness (Table 282), there is considerable overlap
between SRED and NES. Some clinicians consider them to
be two eating disorders at the opposite ends of the spectrum
of awareness.
Treatment
If SRED is medication associated (zolpidem), the medication
should be withdrawn. Patients may not have the behavior
with another medication in the same class (e.g., switch from
zolpidem to eszopiclone). Sometimes, medication-induced
SRED will continue, at least temporarily, even with discon-
tinuation of the offending medication. Topiramate appears
to be the best-documented treatment, although sertraline,
carbidopa/levodopa, and pramipexole have been used
successfully.6872 In one study, the mean dose of topiramate
was 218 mg, although patients may note an improvement at
a 100-mg dose.70 The side effects of topiramate include
weight loss, paresthesias, renal calculi, cognitive dysfunc-
tion, and orthostasis. In one series, up to 41% of patients
discontinued the medication because of side effects. If SRED
is associated with sleepwalking, clonazepam has sometimes
been effective.
Parasomnia, Unspecified
This diagnosis is used on a temporary basis when the para-
somnia is believed to be secondary to a psychiatric diagnosis
but before this diagnosis can be made with certainty.
Parasomnia Due to Drug or Substance
This category can be used when a temporal association
between starting a medication and the onset of a parasomnia
can be documented.
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TABLE 282
Traditional Characteristics of Sleep-Related Eating Disorder and Nocturnal Eating Syndrome
SLEEP-RELATED EATING DISORDER NOCTURNAL EATING SYNDROME
State of consciousness Partial to full arousal state Fully awake during compulsive eating.
Timing of onset Onset out of sleep period Eating between evening meal and onset of
nocturnal sleep
or
Eating during complete awakenings from sleep.
Food Unusual foods or toxic substances Absence of bizarre or atypical foods.
Preference for high-caloric foods
Foods NOT typically preferred during daytime
(e.g., raw food, cat food, frozen food)
Recall Partial or complete amnesia Complete recall.
State in AM Morning anorexia and abdominal distention Morning anorexia can occur, bulimia can occur.
Associated disorders Associated with sleepwalking Associated with eating and psychiatric disorders.
OSA, PLMS
Gender Female 6080% Female < 60%.
Note that in the ICSD-2 diagnostic criteria, there is no requirement for amnesia or an impaired state of consciousness for diagnosis of the sleep-related eating disorder.
ICSD-2 = International Classification of Sleep Disorders, 2nd ed.; OSA = obstructive sleep apnea; PLMS = periodic limb movement during sleep.

Parasomnia Due to Medical Condition BOX 2828

The parasomnia emerges as a manifestation of an underlying Hypnic JerksDiagnostic Criteria

neurologic or medical disorder. RBD is often associated with
Parkinsons disease, Lewy body with dementia, and multiple
system atrophy. An entity known as agrypnia excitia is char-
acterized by generalized motor overactivity, impaired ability
to initiate and maintain sleep (wakeful dreaming), loss of
stage N3 sleep, and autonomic sympathetic activation.
Agrypnia excitia can be found associated with delirium
tremens and fatal familial insomnia.1
OTHER NOCTURNAL BEHAVIORS IN THE
DIFFERENTIAL DIAGNOSIS OF PARASOMNIA
The ICSD-2 classifies a number of nocturnal behaviors under
other categories including sleep-related movement disorders
(bruxism and rhythmic movement disorder) and Isolated
Symptoms and Apparently Normal Variants and Unresolved
Issues (sleep talking, hypnic jerks, propiospinal myoclonus,
hypnagogic foot tremor, and alternating leg movement activ-
ity). Hypnagogic foot tremor, alternating leg movement
activity, and the rhythmic movement disorder are discussed
in Chapter 12.
Sleep Talking (Somniloquy)
Sleep talking is usually reported by the bed partner or
someone asleep near the affected individual.1 Although few
sleep recordings have been performed, sleep talking can arise
from NREM or REM sleep. Vocalizations have been
described associated with sleepwalking, RBD, PTSD, SRED,
A. Patient complains of sudden brief jerks at sleep onset,
mainly affecting the legs or arms.
B. The jerks are associated with at least one of the
following:
i. A subjective feeling of falling.
ii. A sensory flash.
iii. A hypnagogic dream.
C. The disorder is not better explained by another sleep
disorder, medical, or neurologic disorder, mental
disorder, medication use, or substance use disorder
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
on arousal from OSA, and with nocturnal seizures. Sleep
talking has few consequences unless it disturbs the sleep of
others or the content of the talking contains material upset-
ting to the listener (calling out the name of an ex-wife while
the current wife is present).
Hypnic Jerks
Hypnic jerks (sleep starts) are brief total body jerks that
occur at sleep onset.1 These are entirely normal. They may
be associated with a sense of falling. The jerks may affect the
body asymmetrically. There is usually a single jerk at the start
of the sleep episode at transitions from wakefulness to sleep.
Multiple jerks may sometimes occur (Box 2828).
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 Chapter 28 Parasomnias 587

(including those with no known clinical significance), sleep-

Propiospinal Myoclonus
Propriospinal myoclonus at sleep onset (Box 2829) consists
of sudden muscular jerks that occur in transition from wake-
fulness to light sleep. Jerks involve the abdominal and trunk
muscles with spread to involve limbs and neck muscles.73
Differential Diagnosis of Nocturnal Behavior
Table 283 lists notable behavior often seen during the
sleep period. The categories include normal phenomena
BOX 2829
Propiospinal Myoclonus at Sleep Onset
Diagnostic Criteria
A. The patient complains of sudden jerks, mainly of the
abdomen, trunk, and neck.
B. The jerks arise upon relaxed wakefulness and drowsiness
and disappear on mental activation and at sleep onset.
C. The disorder is not better explained by another sleep
disorder, medical, or neurologic disorder, mental
disorder, medication use, or substance use disorder.
From American Academy of Sleep Medicine: ICSD-2 International
Classification of Sleep Disorders, 2nd ed. Diagnostic and Coding Manual.
Westchester, IL: American Academy of Sleep Medicine, 2005.
related movement disorders, parasomnias, psychiatric disor-
ders, and nocturnal seizure disorders.
THE DIFFERENTIAL DIAGNOSIS
OF PARASOMNIAS
In one study of 100 adults referred for evaluation of sleep-
related injury,6 54 had sleep terrors/sleepwalking, 36 had the
RBD, 7 had SRDD, 2 had nocturnal seizures, and 1 had sleep
apnea. Table 283 presents disorders classified as parasom-
nias and other disorders. Some comparisons between the
disorders are presented in Table 284. Nocturnal epilepsy is
discussed in Chapter 27 and psychiatric disorders in Chapter
29. Many prior classifications of nocturnal spells included
the disorders nocturnal paroxysmal dystonia (NPD) and
nocturnal wandering. These are now believed to be mani-
festations of nocturnal frontal lobe epilepsy. Whereas sleep-
related epilepsy is covered in detail in Chapter 27, frontal
lobe epilepsy is briefly discussed here because these patients
typically have seizures confined to the night and typical
manifestations mimic parasomnias.
Nocturnal frontal lobe epilepsy can present as paroxysmal
arousals, NPD, and episodic nocturnal wandering (ENW).74

TABLE 283
Differential Diagnosis of Unusual Behavior Associated with Sleep
GROUP DIAGNOSIS USUAL SLEEP STAGE
Normal sleep phenomenon Sleep starts (hypnic jerks) Sleep onset
Apparently normal variants
Nightmares (REM anxiety attacks) REM >> NREM
Hypnogogic foot tremor Wake or arousal from NREM
Alternating leg movement activity Wake or arousal from NREM
Sleep talking (somniloquy) NREM and REM
Sleep-related movement disorders Periodic limb movements in sleep NREM > REM
Bruxism Any sleep stage, N2 most common
Rhythmic movement disorder Stage W, NREM, REM
Parasomnias Confusional arousal NREM
Sleepwalking (somnambulism) NREM
Sleep terrors NREM
REM sleep behavior disorder REM
Recurrent sleep paralysis REM-wake transition
Nightmare disorders REM >> NREM
Overlap parasomnia NREM and REM
Sleep-related dissociative disorder Occurs from established wake
Enuresis NREM and REM
Catathrenia (sleep-related groaning) REM >> NREM
Psychiatric disorders Panic attacks From wake after arousal from NREM
Posttraumatic stress disorder REM and NREM
Seizure disorders Nocturnal seizures NREM > Wake > REM
NREM = nonrapid eye movement; REM = rapid eye movement.
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TABLE 284
Common Features Associated with Nocturnal Events
NREM PARASOMNIA REM
CONFUSIONAL AROUSALS, BEHAVIOR
SLEEPWALKING, SLEEP TERRORS DISORDER NIGHTMARES SEIZURE
Time of night Childrenearly Late Late > early Any
Adultsearly or late
Sleep stage at start ChildrenStage N3 REM REM NREM > Wake > REM
AdultsStages N2, N3
Screams Yes in sleep terrors Can occur, Rare, talking Rare
No in confusional arousals, talking, yelling more
sleepwalking more common common
Autonomic activation Extreme in sleep terrors Mild Mild Mild
Walking Yessleepwalking Rare No Can occur
Noconfusional arousals, sleep Walking (nocturnal
terrors wandering)
Stereotypical behavior
Confusion after episode Usual No Rare Usual
on awakening
Age Childcommon Adult > 50 yr Any age Adult
Adultless common Male
Episodes also in wake No No No Usual
CNS lesion No Can occur No Common
CNS = central nervous system; NREM = nonrapid eye movement; REM = rapid eye movement.

Paroxysmal arousals typically present during NREM sleep CLINICAL REVIEW QUESTIONS
consisting of a stereotypical series of movements lasting 2 to
20 seconds in which the individuals raise their head, sit up, 1. Which of the following is NOT true about sleepwalking
and look around confused with a frightened expression then in adults?
scream. NPD is characterized by nocturnal coarse move- A. Approximately 60% to 70% have a history of sleep-
ments associated with tonic spasms that often occur multiple walking in childhood.
times per night. The episodes can be violent or be associated B. It can be precipitated by sleep deprivation.
with vocalization. Patients often move the arms and legs with C. Approximately 50% of patients with adult-onset
cycling or kicking movements and sometimes adopt a dys- sleepwalking have psychopathology.
tonic posture of the limbs. ENWs may present with symp- D. It always occurs out of stage N3.
toms similar to sleepwalking and sleep terrors. Patients may
jump out of bed, wander, vocalize, and show violent behavior
2. Which of the following disorders is NOT commonly
during sleep. Treatment with older anticonvulsants such as
associated with RBD?
carbamazepine or newer anticonvulsants such as levetirace-
tam at bedtime is effective. A. Narcolepsy.
Among psychiatric disorders, panic attacks can present B. Parkinsons disease.
as nocturnal spells. Panic attacks occur from wakefulness C. Dementia with Lewy bodies.
after arousal from sleep.20 The individual is alert and D. Alzheimers disease.
the severity builds with intense fear, tachycardia, dyspnea, E. Multiple system atrophy.
chest pain, or flushing. Whereas nocturnal panic attacks
usually occur in patients with known daytime attacks, a
3. Which of the following medications are associated with
few patients may have panic attacks only at night. PTSD
RBD?
patients also may complain of terrifying dreams and may
awaken with episodes similar to sleep terrors.34 They are A. Fluoxetine.
usually not confused on awakening and may have vivid B. Venlafaxine.
dream recall. C. Mirtazapine.
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D. TCAs.
E. All of the above.
4. Which of the following is true about RBD?
A. It typically occurs in the first half of the night.
B. Women > men.
C. It responds to clonazepam in approximately 80% of
patients.
D. It responds to 0.3 to 0.5 mg of melatonin.
E. Dream recall is always present.
5. What characteristic(s) are true about nocturnal panic
attacks?
A. They are associated with autonomic hyperactivity,
tachycardia.
B. The patient is alert during a panic attack.
C. The patient has amnesia for the event.
D. B and C.
E. A and B.
6. Which of the following factors favor nocturnal epilepsy
over a parasomnia?
A. Confusion following the event.
B. Stereotypical behavior.
C. Several episodes per night.
D. Amnesia for the event.
E. B and C.
F. A and B.
7. Which of the following is true concerning the SRED?
A. Patients are not alert during events.
B. Amnesia for SRED events is always present.
C. Prevalence of SRED: men > women.
D. Zolpidem is the medication most often associated
with SRED.
E. Normal foods are eaten.
8. Which of the following characterize events associated
with the exploding head syndrome?
A. They are painless.
B. Men > women.
C. They occur out of NREM sleep.
D. They are not associated with fright.
9. In which of the following situations would a diagnosis
of RBD be indicated?
A. REM sleep without atonia, history of dream
enactment.
B. REM without atonia, body movements on video
PSG during REM sleep.
C. REM without atonia, no body movements during
PSG, no history of dream-enacting behavior.
D. No evidence of REM with atonia, violent movements
out of REM sleep.
Chapter 28 Parasomnias 589
E. A and B.
F. C and D.
10. Which of the following patterns is NOT considered
compatible with RBD?
A. Chin EMGsustained tonic activity during REM
sleep.
B. Chin EMGTMA (phasic) during REM sleep.
C. Leg EMGsustained tonic activity.
D. Leg EMGTMA (phasic).
E. Chin EMGsustained tonic activity and TMA
during REM sleep.
11. Which of the following describes catathrenia?
A. Deep inspiration, prolonged expiratory groan, slow
breathing rate.
B. Long inspiratory groan, slow breathing rate.
C. NREM > REM sleep.
D. Women > men.
E. Patient complains of disturbed sleep.
12. A child was previously dry until age 8 when he began to
have frequent nocturnal enuretic episodes. He also was
noted to snore loudly and to have difficulty concentrat-
ing in classes. Which of the following are true?
A. The patient has secondary enuresis.
B. One of his parents likely had enuresis.
C. OSA should be considered.
D. A and B.
E. A and C.
Answers
1. D. Sleepwalking in adults can occur out of stages N1
and N2 as well as N3.
2. D. Although RBD can occur with patients with
Alzheimers disease, it is not typical of that disorder.
3. E. All of the above.
4. C. RBD responds to clonazepam in about 80% of cases,
although many patients experience side effects. Melato-
nin, often in doses up to 12 mg may also be effective.
RBD is typically a disorder of men older than 50 years
of age. Because this parasomnia occurs out of REM
sleep, the usual timing is the second part of the night.
5. E. Unlike NREM parasomnias, during panic attacks,
patients are alert and do not have amnesia for the event.
Panic attacks may occur out of NREM sleep and be
associated with autonomic hyperactivity and intense
fear.
6. E. Stereotypical behaviors (same manifestations with
every episode) and several episodes per night are more
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590 Chapter 28 Parasomnias
common with nocturnal epilepsy. Confusion after the
event and amnesia can occur with both NREM para-
somnias and many types of nocturnal seizures.
7. D. Zolpidem is the medication most often associated
with SRED. Alertness during event and recall of the
event are highly variable. SRED is much more common
in women than in men. Although normal foods (espe-
cially those high in carbohydrates) may be eaten, frozen
foods and nonfoods are also sometimes consumed.
8. A. Exploding head episodes are painless. They may be
associated with a noise. Episodes occur during drowsi-
ness rather than after arousal from sleep. More women
than men have the syndrome.
9. E. A diagnosis of RBD requires PSG evidence of REM
sleep without atonia and either body movements during
REM sleep noted on a PSG or a history of dream enact-
ment. A PSG showing evidence of REM sleep without
atonia without other findings does not meet diagnostic
criteria. This pattern can simply mean that the patient is
taking an SSRI or similar medication. In pseudo-RBD
(severe untreated OSA), body movements can be noted
during REM sleep with NO evidence of REM sleep
without atonia.29
10. C. Sustained leg EMG activity is not considered evi-
dence of REM sleep without atonia.
11. A. Catathrenia is much more common in REM than in
NREM and is characterized by a prolonged expiratory
groan/moan often with a slow breathing rate. Catathre-
nia is more common in men than in women. This para-
somnia is believed to have no direct consequences for
the patient but can significantly disturb the sleep of the
bed partner.
12. E. Because the patient was previously dry, he has sec-
ondary enuresis. Heritable factors are associated with
primary enuresis. Enuresis can be a manifestation of
OSA.
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Psychiatry and Sleep
Chapter Points
A significant proportion of patients with a sleep
complaint have a psychiatric illness and a significant
number of patients with a psychiatric illness have a
sleep complaint.
Insomnia or hypersomnia nearly every day is one of
the nine major criteria for diagnosis of an MDE.
During an MDE, approximately 80% of patients
complain of symptoms of insomnia (frequent
awakenings, early morning awakening) and 20%
complain of hypersomnia.
PSG during a depressive episode shows a long sleep
latency, reduced sleep efficiency, reduced stage N3, a
short REM latency, a longer first REM period, and a
higher REM density early in the night. Early morning
awakening may also be present.
Insomnia can precede an MDE and is often the last
symptom of depression to resolve. Some but not all
studies suggest that the persistence of sleep
complaints is a risk factor for relapse of depression.
During MEs, the patient reports a decreased need for
sleep (feeling rested on a few hours of sleep). Sleep
loss can precipitate an ME.
Hypomanic episodes have characteristics similar to
those of MEs except for the following three conditions:
severe impairment is not present, hospitalization is not
necessary, and there are no psychotic features. If any
of the three are present, the episode is considered an
ME.
A summary of duration criteria for the mood episodes:
MDE: 2 weeks.
ME: 1 week.
Mixed episode: 1 week.
Hypomanic episode: 4 days.
Bipolar disorder I requires:
A current (or recent) hypomanic, ME, mixed episode,
or MDE.
If the current episode is hypomanic or an MDE,
there must be history of a prior mixed episode
or ME.
Note that, unlike diagnostic criteria for bipolar disorder
II, the presence of at least one MDE is not required.
Chapter 29
Bipolar disorder II consists of at least one hypomanic
episode, one or more depressive episodes, and no
history of current (or prior) MEs or mixed episodes.
Relapse rates for bipolar disorder patients are very
high, even on maintenance therapy. Bipolar disorder is
a significant risk factor for suicide.
Most patients with nocturnal panic attacks have similar
episodes during the day. However, panic attacks can
occur mainly at night and must be differentiated from
NREM parasomnias such as sleep terrors.
The treatment of panic disorder includes behavioral
psychotherapy/relaxation techniques, an SSRI (e.g.,
paroxetine or sertraline), and an antianxiety
medication such as alprazolam or clonazepam. The
SSRI is typically started in a low dose in combination
with an antianxiety medication to prevent initial
worsening of symptoms. The antianxiety medication
can later be tapered in many cases.
Disturbing nightmares are a significant problem
impairing sleep in PTSD. Imagery rehearsal therapy
and prazosin are two relatively new treatment options.
Psychiatric disorders are among the most common health
problems, with over 15% to 20% of Americans being treated
for a significant psychiatric illness in any given year.1 Almost
one third of individuals with significant complaints of
insomnia or hypersomnia show evidence of psychiatric
disorders.25 Psychiatric disorders account for the largest
diagnostic category for patients with sleep complaints. Con-
versely, sleep complaints are part of the diagnostic criteria
for many psychiatric disorders and are a source of consider-
able morbidity. The psychiatric disorders commonly affect-
ing sleep (or vice versa) are listed in Box 291.
MOOD DISORDERS
Mood disorders are the most common category of psychiat-
ric disorders followed by anxiety disorders. The mood dis-
orders include major depressive disorder (MDD) and the
bipolar disorders. The mood disorders are defined on the
basis of the occurrence of mood episodes. Several types of
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594 Chapter 29 Psychiatry and Sleep
BOX 291
Psychiatric Disorders Commonly Affecting Sleep
MOOD DISORDERS
Major depressive disorder
Bipolar disorder I
Bipolar disorder II
ANXIETY DISORDERS
Panic disorder
Posttraumatic stress disorder
Generalized anxiety disorder
mood episodes (major depressive, manic, hypomanic, and
mixed) are defined later. When mood episodes occur in a
temporal pattern together with other diagnostic features,
they define the characteristics of the mood disorder. Note
that all mood episodes with the exception of hypomania
have impairment as a criterion.
Depression Questionnaires and Severity
Rating Scales
A number of depression scales are available for use by the
sleep clinician in helping evaluate patients for possible
depression or measuring improvement with treatment.
The Beck Depression Inventory was mentioned in Chapter
25 on insomnia.6 The Hamilton Depression Scale (HAMD)
is a 17, 21, or 24 question instrument that is widely used for
research.7 The Montgomery-sberg Depression Rating Scale
(MADRS) is a 10-item diagnostic questionnaire used to
measure the severity of depressive episodes in patients.8 It
was developed to be sensitive to the changes brought on by
antidepressants and other forms of treatment. The Patient
Health Questionnaire (PHQ-9) is a short 9-question instru-
ment (Appendix 291)9 that the patient can quickly fill out
and is easy to use. The PHQ-9 has been validated and
may be used to screen patients with sleep disorders for
depression.
Mood Episodes
Major Depressive Episode
A major depressive episode (MDE; Box 292) is defined by
five (or more) of the following nine symptoms having been
present during the same 2-week period and representing a
change from previous functioning; at least one of the symp-
toms is either (1) depressed mood or (2) loss of interest or
pleasure (Diagnostic and Statistical Manual of Mental Dis-
orders, 4th edition [DSM-IV]).2
1. Depressed mood.*
2. Markedly diminished interest or pleasure.*
*Essential symptoms.
BOX 292
Major Depressive Episode
A. Five (or more) of the following nine symptoms have
been present during the same 2-week period and
represent a change from previous functioning; at least
one of the symptoms is either (1) depressed mood or (2)
loss of interest or pleasure.
1. Depressed mood, present most of the day, nearly
every day, as indicated by either subjective report
(e.g., feels sad or empty) or observation made by
others (e.g., appears tearful). Note: In children and
adolescents can be irritable mood.
2. Markedly diminished interest or pleasure in all, or
almost all, activities most of the day, nearly every day
(as indicated by either subjective report or
observation made by others).
3. Significant weight loss when not dieting or weight
gain (e.g., change of > 5% of body weight in a month),
or decrease or increase in appetite nearly every day.
4. Insomnia or hypersomnia nearly every day.
5. Psychomotor agitation or retardation present
nearly every day (observable by others, not merely
subjective feelings of restlessness or being slowed
down).
6. Fatigue or loss of energy nearly every day.
7. Feelings of worthlessness or excessive or
inappropriate guilt (which may be delusional)
nearly every day.
8. Diminished ability to think or concentrate, or
indecisiveness nearly every day.*
9. Recurrent thoughts of death (not just fear of dying),
recurrent suicidal ideation without a specific plan, or
a suicide attempt or specific plan for committing
suicide.
B. Symptoms do not meet criteria for a mixed episode.
C. Symptoms cause clinically significant distress or
impairment in social, occupational, or other important
areas of functioning.
D. Symptoms are not due to the direct physiologic effects
of a substance (e.g., drug of abuse, a medication, or
other treatment) or general medical condition (e.g.,
hypothyroidism).
E. Symptoms are not better accounted for by bereavement
(i.e., after the loss of a loved one), the symptoms persist
for longer than 2 months or are characterized by
marked functional impairment, morbid preoccupation
with worthlessness, suicidal ideation, psychotic
symptoms, or psychomotor retardations.
*Either by subjective report or observed by others.
Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.
3. Significant weight loss, when not dieting, or weight gain,
or decrease or increase in appetite.
4. Insomnia or hypersomnia nearly every day.
5. Psychomotor agitation or retardation nearly every day
(observable by others, not merely subjective feelings or
restlessness or being slowed down).
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BOX 293 BOX 294

Subtypes of Depressive Episodes Sleep and Major Depressive Episodes
MELANCHOLIC Symptoms
(RETARDED) SUBTYPE ATYPICAL (ANXIOUS) SUBTYPE 80% of depressive episodes are associated with
Minimal mood Mood reactivity must be insomnia
reactivity present Early AM awakening.
Look depressed or Can feel much better or even Frequent awakening.
flat during interview normal in social situations 1520% hypersomnia.
Insomnia Do not always look PSG findings
Loss of appetite and depressed during interview Prolonged sleep latency.
weight loss At least two of four additional Increased wake, early AM awakening, frequent
Severe anhedonia symptoms: awakenings.
Inability to find Hypersomnia Decreased stage N3, decreased N3 in the early part of
pleasure in anything Hyperphagia/weight gain the night.
Diurnal variability Rejection sensitivityfear of REM abnormalities.
Worse in morning negative social evaluation
Short REM latency.
More common in Laden fatigue
Increased REM density.
older age groups More likely in younger age
Particularly in groups Increased REM early in the night.
elderly and In one study, 60% of adults Increased REM (%TST).
medically ill with atypical subtype had MSLTdoes NOT demonstrate severe sleepiness.
bipolar II disorder Sleep abnormalities may persist after remission.
Persistent abnormalities may be associated with risk of
recurrence.
MSLT = multiple sleep latency test; PSG = polysomnography; REM = rapid
6. Fatigue or loss of energy. eye movement; TST = total sleep time.
7. Feelings of worthlessness or excessive or inappropriate
guilt (which may be delusional) nearly every day (not
merely self-reproach or guilt about being sick).
8. Diminished ability to think or concentrate or indecisive- and the atypical subtype is more characteristic of bipolar
ness nearly every day. depressive episodes.
9. Recurrent thoughts of death (not just fear of dying),
recurrent suicidal ideation without a specific plan, or a Impact of MDE on Sleep The impact of an MDE on sleep is
suicide attempt or specific plan for committing suicide. summarized in Box 294. A sleep complaint (insomnia or
hypersomnia) is one of the primary diagnostic criteria for an
In order to meet criteria for an MDE, symptoms must not MDE. Nearly 80% of depressive episodes are associated with
meet criteria for a mixed episode, must cause significant insomnia.3,4 The insomnia complaints include early morning
distress or impairment, and are not a result of another awakening and frequent awakenings. However, up to 15% to
process or medication/substance. In addition, the symptoms 20% of patients complain of hypersomnia during an MDE.
are not explained by bereavement. An MDE can occur in The polysomnography (PSG) findings in patients during an
either bipolar disorders or unipolar depression (MDD). A MDE4,5 include a prolonged sleep latency, increased wake
useful mnemonic for symptoms of depression = depressed after sleep onset, decreased stage N3, and rapid eye move-
mood + SIGECAPS = Sleep, Interest, Guilt, Energy, Concen- ment (REM; stage R) abnormalities. The stage R abnor-
tration, Appetite, Pleasure, and Suicidality. malities include a short REM latency, an increased length
MDEs are sometimes divided into melancholic and atypi- of the first REM episode, and an increased REM density
cal subtypes (Box 293). The melancholic subtype is associ- in the early part of the night. Recall that the REM density
ated with insomnia whereas hypersomnia is characteristic (number of REMs per time) is typically low during the first
of the atypical subtype. The melancholic subtype usually has REM episodes. Symptoms of insomnia or PSG abnormalities
worse symptoms in the morning. An atypical depressive may persist after remission of depression.5,1014 Rush and
episode is also characterized by mood reactivity (ability for coworkers10 found a short REM latency (<65 min) in 11/13
mood to temporarily improve in response to a positive or patients during active depression, and in those 11 patients,
stimulating situation), increased appetite and weight, laden a short REM latency persisted in 8 after clinical remission.
fatigue (a sense of heaviness or being weighed down), and Dombrovski and colleagues14 found that anxiety and possi-
rejection sensitivity (fear of social rejection). Unipolar bly residual sleep disturbance predicted early recurrence.
depressive episodes are more often of the melancholic type However, Yang and associates15 did not find that persistent
sleep disturbance predicted recurrence. Even if patients with
an MDE complain of hypersomnia, the multiple sleep latency
test (MSLT) does not usually reveal severe sleepiness.3,4,16

Either by subjective report or observed by others.

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596 Chapter 29 Psychiatry and Sleep
Manic Episode
Manic episodes (MEs) are distinct periods of abnormally
and persistently elevated, expansive, or irritable mood,
lasting at least 1 week (or any duration if hospitalization is
necessary) (Box 295). If the mood is irritable, four of the
following are needed, otherwise three of the following2:
1. Inflated self-esteem or grandiosity.
2. Decreased need for sleep (e.g., feels rested after 3 hr of
sleep).
3. More talkative than usual or pressure to keep talking.
4. Flight of ideas or subjective experience that thoughts are
racing.
5. Distractability (i.e., attention too easily drawn to unim-
portant or irrelevant external stimuli).
6. Increase in goal-directed activity (either socially, at work
or school, or sexually) or psychomotor agitation.
BOX 295
Manic Episode
A. Distinct period of abnormally and persistently elevated,
expansive, or irritable mood, lasting at least 1 week (or
any duration if hospitalization is necessary).
B. During the period of mood disturbance, three (or
more) of the following symptoms have persisted (four
if the mood is only irritable) and have been present to
a significant degree:
1. Inflated self-esteem or grandiosity.
2. Decreased need for sleep (e.g., feels rested after 3 hr
of sleep).
3. More talkative than usual or pressure to keep talking.
4. Flight of ideas or subjective experience that
thoughts are racing.
5. Distractability (i.e., attention too easily drawn to
unimportant or irrelevant external stimuli).
6. Increase in goal-directed activity (either socially, at
work or school, or sexually) or psychomotor
agitation.
7. Excessive involvement in pleasurable activities
that have a high potential for painful consequences
(e.g., engaging in unrestrained buying sprees, sexual
indiscretions, or foolish business investments).
C. Symptoms do not meet criteria for mixed episode.
D. Mood disturbance is sufficiently severe to cause
marked impairment in occupational function
or in usual social activities or relationships with
others or to necessitate hospitalization to
prevent harm to self or others, or there are
psychotic features.
Manic episodes cause marked impairment or have
psychotic features (in contrast, hypomania mood
disturbance does NOT cause marked impairment, does NOT
necessitate hospitalization, and has NO psychotic features).
Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.
7. Excessive involvement in pleasurable activities that have
a high potential for painful consequences (e.g., engaging
in unrestrained buying sprees, sexual indiscretions, or
foolish business investments).
In MEs, the symptoms do not meet criteria for a mixed
episode (defined later). The disturbance is sufficiently severe
to cause marked impairment in occupational function or
in usual social activities or relationships with others or to
necessitate hospitalization to prevent harm to self or
others, or there are psychotic features. Note that the symp-
toms noted previously are essentially the same for hypo-
mania episodes (discussed in a later section), BUT in
hypomania, there is NO marked impairment, need for hos-
pitalization, or psychotic features.
Impact of Mania on Sleep MEs are associated with marked
insomnia, but the patient awakens refreshed after a few
hours of sleep. PSG findings include reduced stage N3, a
short REM latency, and an increased REM density.11,1719 Of
note, sleep loss can trigger MEs20,21 (Box 296).
Mixed Episode
In mixed episodes, criteria are met both for an ME and for
an MDE (except for duration) nearly every day during at
least a 1-week period.2 The disturbance is sufficiently severe
to cause marked impairment in occupational function or
in usual social activities or relationships with others or to
necessitate hospitalization to prevent harm to self or others,
or there are psychotic features. Symptoms are not due to the
direct physiologic effects of a substance (e.g., drug of abuse,
a medication, or other treatment) or general medical condi-
tion (e.g., hypothyroidism). The mixed episode combines
symptoms of both mania and depression. The patient may
be effusive and grandiose one moment and crying the next
(Box 297).
Hypomanic Episode
A hypomanic episode is a distinct period of persistently
elevated, expansive, or irritable mood, lasting throughout at
BOX 296
Manic/Hypomanic Episodes and Sleep
MANIC EPISODES
Marked insomnia.
Refreshed with only a few hours of sleep.
PSG findings
Reduced stage N3.
Short REM latency.
Increased REM density.
Sleep loss can trigger mania.
HYPOMANIC EPISODES
Report of decreased sleep need.
PSG = polysomnography; REM = rapid eye movement.
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BOX 297
Mixed Episode
A. Criteria are met both for a manic episode and for a
major depressive episode (except for duration) nearly
every day during at least a 1-week period.
B. Mood disturbance is sufficiently severe to cause
marked impairment in occupational function or in
usual social activities or relationships with others or to
necessitate hospitalization to prevent harm to self or
others, or there are psychotic features.
C. Symptoms are not due to the direct physiologic effects
of a substance (e.g., drug of abuse, a medication, or
other treatment) or general medical condition (e.g.,
hypothyroidism).
Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.
least 4 days, that is clearly different from the usual nonde-
pressed mood (Box 298).2 During the period of mood dis-
turbance, three (or more) of the following symptoms have
persisted (four if the mood is only irritable) and have been
present to a significant degree:
1. Inflated self-esteem or grandiosity.
2. Decreased need for sleep (rested on 3 hr of sleep).
3. More talkative than usual or pressure to keep talking.
4. Flight of ideas or subjective experience that thoughts are
racing.
5. Distractability.
6. Increase in goal-directed activity or psychomotor
agitation.
7. Excessive involvement in pleasurable activities that
have a high potential for painful consequences (e.g.,
buying sprees, sexual indiscretions, or foolish business
investments).
Episodes of hypomania are associated with an unequivo-
cal change in functioning that is uncharacteristic of the
person when she or he is not symptomatic. Of note, the
disturbance in mood and the change in functioning are
observable by others. Although all the previous statements
are similar to those of MEs, the following differentiate hypo-
mania from mania. The hypomania episode is NOT SEVERE
enough to cause marked impairment in social or occupa-
tional function, or to necessitate hospitalization, and there
are NO psychotic features (no delusions or hallucinations
are present). Note that a diagnosis of a hypomanic episode
requires a minimum duration of 4 days whereas the
minimum duration of symptoms for diagnosis of an ME
is 1 week (see Box 298).
Impact of Hypomania on Sleep Complaint of insomnia (mainly
short sleep duration) or decreased need for sleep. In general,
patients with hypomania report similar sleep symptoms as
mania, but they are not as severe and do not cause the patient
significant distress. In fact, patients may enjoy more energy
and a lower sleep requirement.
Chapter 29 Psychiatry and Sleep 597
BOX 298
Hypomanic Episode
A. A distinct period of persistently elevated, expansive, or
irritable mood, lasting throughout at least 4 days, that is
clearly different for the usual nondepressed mood.
B. During the period of mood disturbance, three (or more)
of the following symptoms have persisted (four if the
mood is only irritable) and have been present to a
significant degree:
i. Inflated self-esteem or grandiosity.
ii. Decreased need for sleep (rested on 3 hours of
sleep).
iii. More talkative than usual or pressure to keep
talking.
iv. Flight of ideas or subjective experience that
thoughts are racing.
v. Distractability.
vi. Increase in goal-directed activity or psychomotor
agitation.
vii. Excessive involvement in pleasurable activities that
have a high potential for painful consequences (e.g.,
buying sprees, sexual indiscretions, or foolish
business investments).
C. The episode is associated with an unequivocal change
in functioning that is uncharacteristic of the person
when not symptomatic.
D. The disturbance in mood and the change in functioning
are observable by others.
E. The episode is NOT SEVERE enough to cause marked
impairment in social or occupational function, or to
necessitate hospitalization, and there are NO
psychotic features.
F. The symptoms are not due to the direct physiologic
effects of a substance (e.g., a drug of abuse, a
medication, or other treatment) or a general medical
condition (e.g., hypothyroidism).
Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.
Summary of Minimum Episode Durations
MDE: 2 weeks.
ME: 1 week.
Mixed episode: 1 week.
Hypomanic episode: 4 days.
Mood Disorders
The major mood disorders are listed in Box 299. This is not
a complete list. For additional disorders refer to the DSM-
IV.2 These mood disorders are diagnosed based on occur-
rence of mood episodes (Fig. 291).
Major Depressive Disorder
The MDDs include (1) MDDsingle episode or (2) MDD
recurrent (Box 2910).2 To be considered separate episodes,
the depressive episodes must be separated by at least 2
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598 Chapter 29 Psychiatry and Sleep

MOOD EPISODES
WITH MINIMUM TIME
CRITERIA (DSM-IV) MOOD DISORDERS

Euthymia Major depression, recurrent

Major depressive episode (2 weeks)

Bipolar 1 disorder
Manic episode (1 week)
Bipolar 1 disorder
Mixed episode (1 week)

Hypomania episode (4 days) Bipolar 1 disorder, mixed state

Bipolar 2 disorder

Cyclothymia (highs and lows too

brief to meet criteria of hypomania or
major depressive episode)

FIGURE 291 Schematic of episodes (showing minimum durations) and examples of mood disorders (elevations about and below
baseline represent elevated or depressed mood). Adapted from Priviter MR, Lness JM: Psychiatry Mentor, 2nd ed. Philadelphia: FA Davis,
2008, p. 121.

BOX 299 BOX 2910

Mood Disorders
I. Major depressive disorder (no hypomania, mixed, manic
episodes)
1. Major depressive disorder, single episode
2. Major depressive disorder, recurrent
II. Dysthmic disorder
III. Bipolar disorder I (at least one manic or mixed episode)
IV. Bipolar disorder II (at least one hypomanic episode, one
or more MDEs, and no manic or mixed episodes)
V. Cyclothymic disorder
consecutive months in which diagnostic criteria for MDE
are not met. In MDD, there is NO history of a manic, mixed,
or hypomanic episode. MDD is sometimes called unipolar
depression.
Sleep and MDD At least 60% to 80% of patients with an MDD
report at least one of the following sleep complaints: diffi-
culty falling asleep (38%), frequent awakenings (39%), or
early morning awakening (41%) (Box 2911).3,13 Subjective
complaints of insomnia may improve but are not necessarily
normalized with remission from major depression.1215
Insomnia is often the last symptom to improve in patients
treated for MDD. In addition, insomnia is the most common
residual complaint in patients who have recovered from
depression. Some studies have suggested that the persistence
of sleep disturbance during remission from depression is
predictive of a relapse.13,14 However, a recent double-blind
withdrawal of fluoxetine (FLX) after successful treatment15
was unable to show a predictive value of residual sleep dis-
turbance for the risk of recurrence of depression. Patients
having a response to FLX during an open-label study received
placebo or FLX during withdrawal. Sleep components of the
Major Depressive Disorder
1. Major depressive disorder, single episode
A. Presence of a single major depressive episode.
B. There has NEVER been a manic, mixed, or hypomanic
episode.
2. Major depressive disorder, recurrent
A. Presence of two or more depressive episodesto be
considered separate episodes, there must be an
interval of at least 2 consecutive months in which
criteria for major depressive episodes are NOT met.
B. There has NEVER been a manic, mixed, or hypomanic
episode.
Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.
BOX 2911
Sleep in Major Depressive Episode
Insomnia in 65%frequently sleep-maintenance
insomnia, early AM awakening.
Insomnia may precede the depressive episode.
Insomnia is the most common residual symptom after
remission.
Residual insomnia may be predictive of recurrence of
depression. However, a recent study did not replicate this
finding.
HAMD were used to determine whether residual sleep com-
plaints correlated with an increased chance of relapse. No
sleep complaint was associated with higher rate of relapse of
depression.
Depression and insomnia appear to have a reciprocal
relationship because insomnia frequently precedes the
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onset of depression and has been found to be strongly
predictive of future depressive episodes. Individuals with
persistent insomnia have been found to be 4 to 10 times
more likely to subsequently develop depression than those
with short-term insomnia or no insomnia.22 Patients with
depression and persistent insomnia are 1.8 to 3.5 times
more likely to remain depressed, compared with patients
with no insomnia.23
Of interest, sleep deprivation or restriction has been
found to have an acute antidepressant effect on patients with
unipolar depression.24,25 With recovery sleep, 50% to 80% of
patients have a relapse. As noted previously, sleep loss can
also precipitate mania in some patients.
Differential Diagnosis of Sleep Disturbance in MDE Differential
diagnosis: If insomnia complaints are prominent, psycho-
physiologic insomnia or inadequate sleep hygiene should be
considered. If hypersomnia complaints are prominent, then
one should consider obstructive sleep apnea (OSA), narco-
lepsy, or insufficient sleep.
Treatment of Depression A detailed discussion of the treat-
ment of depression is beyond the scope of this chapter. Psy-
chotherapy and medications are often used alone or in
combination. Many antidepressants are available.2633 Often,
the choice is based on side effects and which symptoms are
most prominent (anxiety, fatigue). Individual patients may
respond to a different medication if treatment with an initial
antidepressant is not successful. It is important to get a good
drug history. If a patient previously responded to a medica-
tion, he or she is likely to have a good response again (Table
291). The older tricyclic antidepressants (TCAs) block the
reuptake of serotonin and norepinephrine and are effective
treatment for depression. However, the TCAs are not selec-
tive in the blockade of receptors and are associated with
prominent anticholinergic side effects (constipation, dry
mouth). They are also lethal in overdose. The selective sero-
tonin reuptake inhibitors (SSRIs) are safer in overdose and in
general have fewer side effects than TCAs. They vary in a
number of properties. For example, the half-life of FLX is
very long. The SSRIs can cause either daytime sedation or
insomnia. If they cause insomnia, they should be given in the
morning. If they cause sedation, they should be given at
bedtime. SSRIs can also have prominent sexual side effects or
result in weight gain in some patients. There is some evidence
that escitalopram (Lexapro) is the most effective (or at least
as effective)29,30 for unipolar depression as other commonly
used antidepressants and is well tolerated. Escitalopram also
has fewer drug interactions than many other antidepressants.
Some studies suggest that citalopram (racemic) is less effec-
tive than escitalopram. If escitalopram cannot be used due to
financial issues, sertraline is a good alternative.
Bupropion is a unique medication with serotonin and
dopamine uptake blocking effects. It has fewer sexual side
effects than SSRIs and weight gain is less of a problem. It
must be taken two or three times a day unless used in the
extended-release form (Wellbutrin XL). It should not be
used in patients with a seizure disorder. Venlafaxine (Effexor)
Chapter 29 Psychiatry and Sleep 599
TABLE 291
Depression Treatment Strategy
UNIPOLAR DEPRESSIONGENERAL APPROACH
Escitalopram (Lexapro)
Highest response rate in some meta-analyses.
Favorable side effect profile.
Wellbutrin XL (bupropion, generics require multiple doses,
possibly less effective)
Some clinicians feel less effective for depression but
may be better tolerated than SSRIs.
Best side effect profile.
No weight gain.
Minimal sexual side effects.
Sertraline (Zoloft)
Possibly most effective generic SSRI, well tolerated.
Other SSRIs
Fluoxetine (long half-life, can be used for SNRI
withdrawal side).
Citalopram (Celexa).
Paroxetine (Paxil) if anxiety a major component, sedating.
PROMINENT MELANCHOLIC MANIFESTATIONS
Tricyclic antidepressants classic treatment
Affects both NE and 5HT.
More side effects, lethal in overdose.
Good initial antidepressant choices
Wellbutrin XL (bupropion).
Venlafaxine (Effexor) (prominent withdrawal side effects).
Mirtazapine (Remeron) (helps with sleep).
Augmentation strategies based on primary residual
symptoms
Treat insomnia (see Table 293), anxiety, appetite.
Treat anergy/cognitive deficits
Stimulant, modafinil, armodafinil*
PROMINENT ATYPICAL FEATURES
Monoamine oxidase inhibitor classic treatment
All three monoamines5HTP, DA, and NE.
Rarely used due to required dietary restrictions, cannot
be used with SSRIs (serotonin syndrome).
Start with SSRI (tricyclics less effective).
Augmentation usually necessary
Aripiprazole, Wellbutrin XL.
Stimulant, modafinil*, armodafinil*.
*Not FDA approved for treatment of depression.
DA = dopamine agonist; 5HT = serotonin; 5HTP = 5-hydroxy-L-tryptophan;
NE = norepinephrine; SNRI = selective norepinephrine reuptake inhibitor;
SSRI = selective serotonin reuptake inhibitor.
and desvenlafaxine (Pristiq) block reuptake of serotonin at
lower doses and serotonin and norepinephrine at higher
doses (selective norepinephrine reuptake inhibitors [SNRIs]).
They are very effective antidepressants but can increase
anxiety and cause a severe withdrawal syndrome if not
tapered. Venlafaxine and desvenlafaxine can also increase
blood pressure. Duloxetine (Cymbalta) blocks uptake of
serotonin and norepinephrine (SNRI) and is used both as an
antidepressant and to treat chronic pain (U.S. Food and Drug
Administration [FDA] approved for treatment of fibromyal-
gia). Mirtazapine (Remeron) is a unique medication that
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TABLE 292
Factors to Consider in Choosing an Antidepressant
Previous medication history
Use a medication with a previous good response (unless
side effects)
Avoid a medication if previous negative response or
negative response to two or more in subclass
Choose best fit for depression subtype
Ability to treat co-morbid psychiatric or medical disorder
Patient preference
Side effect profile
Cost issues
blocks histamine, central alpha 2 receptors, and 5HT2 and
5HT3 serotonin receptors. In low doses (7.515 mg), mir-
tazapine is more sedating compared with higher doses. The
typical effective antidepressant dose is 30 to 45 mg. Mir-
tazapine, like bupropion, is less likely to cause sexual side
effects but can cause significant weight gain. Mirtazapine
may help patients with anxiety. Blockade of 5HT2 receptors
may improve sleep quality.
An approach for choosing an antidepressant for treatment
of depression is listed in Table 292. If the patient has promi-
nent melancholic or atypical features, one might consider
different medications. If the patient does not respond to an
effective dose of the initial medication, either trial of another
medication or the addition of another agent (augmentation)
could be considered. Note that the serotonin syndrome
(agitation, tachycardia, hyperthermia) can rarely occur when
two medications blocking serotonin re-uptake are used
together. The syndrome is most common with use of an SSRI
+ MAOI (contraindicated). Do not start an SSRI until a
MAOI has been stopped for 21 days. Do not start a MAOI
unless an SSRI has been stopped for up to five weeks (depend-
ing on SSRI half-life).
A detailed discussion of the use of second-generation
antipsychotics (SGAs)3436 (e.g., quetiapine, aripiprazole) or
alerting agents (modafinil)37 for augmentation of treatment
of depression is beyond the scope of this chapter. However,
the reader should be aware that such medications are being
used for this purpose. Aripiprazole (Abilify) is FDA approved
for adjunctive therapy of major depression. This medication
tends to cause less metabolic side effects (weight gain) than
other SGAs. Quetiapine (Seroquel) is approved as both an
adjunctive and a single agent treatment for depression.35,36
Effects of Antidepressants on Sleep A discussion of the effects
of antidepressants on sleep (Table 293) is complicated by
the fact that the results can vary depending on whether
normal or depressed individuals are studied. The acute and
chronic effects may also vary.27,28 The literature is somewhat
conflicting on the effects of a few medications. In general,
antidepressants increase the REM latency and decrease the
amount of REM sleep. Bupropion is one of the few medica-
tions that can actually increase the amount of REM sleep,
although it increases the REM latency (at least in depressed
patients). Nefazodone is a sedating antidepressant that also
tends to increase REM sleep.38 It can cause severe hepatotox-
icity and is rarely used today. Mirtazapine also has been
reported to be associated with no or only mild reduction in
the amount of REM sleep. The monoamine oxidase inhibi-
tors (MAOIs) are less commonly used but are the most
powerful suppressors of REM sleep. In general, sedating
antidepressants have a beneficial effect on sleep efficiency
whereas nonsedating antidepressants tend to decrease sleep
efficiency. Of note, if patients respond to an antidepres-
sant, their subjective estimate of their sleep quality may
improve even if objective sleep quality by PSG does not.
A study comparing fluoxetine and nefazodone showed sub-
jective improvements in sleep quality with both medications
but only patients on the sedating nefazodone had objective
improvements in sleep.38
Pharmacotherapy for Co-morbid Insomnia of Psychiatric
Disorders Patients with an MDD frequently have prominent
co-morbid insomnia. In such patients, one might choose to
use (1) a sedating antidepressant at antidepressant doses
(e.g., mirtazapine 3045 mg qhs), (2) the combination of an
effective nonsedating antidepressant (at antidepressant
doses) and a sedating antidepressant at low doses, (3) the
combination of an effective nonsedating antidepressant and
a benzodiazepine receptor agonist [BZRA] hypnotic), or (4)
the combination of an antidepressant and a sedating atypical
antipsychotic (quetiapine). Sedating antidepressants and
antipsychotics commonly used for their hypnotic effect are
listed in Table 294. For information on BZRA hypnotics,
see Chapter 25.
Several sedating antidepressants are used in lower than
antidepressant doses for their sedating properties. Doxepin
is a sedating antidepressant but has anticholinergic side
effects. It has been used in low doses (25 mg) as a hypnotic.
It has recently been approved by the FDA for sleep mainte-
nance in very low doses (3, 6 mg Silenor). Silenor is much
more expensive than generic doxepin. Trazodone is used in
low doses (50 mg) as a hypnotic but rarely in higher doses
as an antidepressant. Trazodone can be used in combination
with an SSRI to reduce antidepressant-associated insomnia.39
Trazodone can rarely cause priapism but has minimal anti-
cholinergic side effects compared with sedating TCAs.
Because of the lack of anticholinergic side effects and avail-
ability of generic medication, trazodone is widely used as a
hypnotic. As discussed in Chapter 25, the evidence for its
hypnotic efficacy in patients who are not depressed is limited.
The utility of using the combination of an antidepressant
and a BZRA has recently been studied using placebo-
controlled trials. Fava and coworkers40 studied a group of
patients with both MDD and insomnia. The combination of
FLX and placebo was compared with FLX + 3 mg of eszopi-
clone. Co-administration of eszopiclone resulted in improved
subjective sleep latency, wake after sleep onset (WASO), and
total sleep time compared with FLX alone. Although this
result was not unexpected, a surprising finding was that
there was also greater improvement in depression at 8 weeks
with the combination of FLX and eszopiclone (Fig. 292). A
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TABLE 293
Effects of Antidepressants on Sleep
CONTINUITY STAGE N3 REM REM LATENCY SEDATION
TCAs
Amitriptyline ++++
Doxepin ++++
Imipramine ++
Nortriptyline ++
Desipramine +
Clomipramine
MAOIs
Phenelzine
SSRIs
Fluoxetine
Paroxetine +
Sertraline +
Citalopram +
Escitalopram +
SNRIs
Venlafaxine ++
Desvenlafaxine Same
Duloxetine Same
ATYPICAL
Bupropion
Trazodone ++++
Mirtazapine 3+ (low doses)
Up arrows = increased; down arrows = decreased; horizontal arrows = no or minimal change; plus signs (14) = increasing amount of sedation; MAOIs = monoamine
oxidase inhibitors; REM = rapid eye movement; SNRIs = selective norepinephrine reuptake inhibitors; SSRIs = selective serotonin reuptake inhibitors; TCAs = tricyclic
antidepressants.

Response Remission FIGURE 292 Eszopiclone + fluoxetine resulted in a

(%50% HAM-D17 decrease) (HAM-D17  7) significantly greater improvement in the Hamilton Depression
70 70 Scale (HAM) at 8 weeks as determined by both relapse and
P = .009 Placebo+fluoxetine
remission compared with placebo + fluoxetine. From Fava M,
60 59 60 Eszopiclone+fluoxetine
McCall V, Krystal A, et al: Eszopiclone co-administered with
fluoxetine in patients with insomnia coexisting with major
50 48 50 P = .03
depressive disorder. Biol Psychiatry 2006;59:10521060.
Percent of patients

42
P = .14
40 36 40
33
30
30 30 P = .29
22
20 20 19

10 10

0 0
Week 4 Week 8 Week 4 Week 8
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TABLE 294
Antidepressants and Atypical Antipsychotics Used for Sleep
NAME GENERIC DOSE HYPNOTIC
(BRAND NAME) FORMS DOSE COMMENTS NOTABLE SIDE EFFECTS
Trazodone 50, 100 mg 25100 mg qhs Less anticholinergic side Priapism (1/8000 males)
effects than TCAs Postural hypotension
T 9 (314) hr
Mirtazapine 15, 30 mg 7.515 mg qhs T 2040 hr Weight gain
(Remeron) Higher doses possibly less sedating
TCAs
Amitryptyline 10, 25, 50 mg 1025 mg qhs T 1026 hr metabolite Dry mouth, constipation
(Elavil) active (nortriptyline) QT prolongation
Doxepin 10, 25, 50 110 mg (elixir) T 68 hr Dry mouth, constipation
(Sinequan) 10 mg/mL 25 mg qhs
Doxepin 3, 6 mg 6 mg qhs T 68 hr FDA approved for sleep-maintenance
(Silenor) 3 mg qhs elderly insomnia
Cimetidine increases drug levelsmax dose
of doxepin should not exceed 3 mg
Sertraline can also increase levels of doxepin
SEDATING ANTIPSYCHOTIC MEDICATIONS
Quetiapine 25, 50, 100 12.550 mg qhs T 6 hr Headache, dizziness
(Seroquel) Intermediate acting Neuroleptic syndrome
Tardive dyskinesia
Long QT
Lens change
FDA = U.S. Food and Drug Administration; TCAs = tricyclic antidepressants.

similar trial with zolpidem found improvement in sleep but BOX 2912
no evidence of greater improvement in depression.41 Dysthmic Disorder
In patients with a history of past or current alcohol or
A. Depressed mood for most of the day, for more days than
benzodiazepine dependence, the use of BZRAs is prob-
not, as indicated either by subjective account or
lematic. For these patients, use of ramelteon (a melatonin observation by others, for at least 2 years.
receptor agonist with no abuse potential) or a sedating anti- B. Presence while depressed of two or more of the
depressant may be the best treatment option. Ramelteon is following:
approved only for sleep-onset insomnia and is not useful to i. Poor appetite or overeating.
improve sleep maintenance. It should NOT be used with the ii. Insomnia or hypersomnia.
SSRI luvoxamine, which causes increased melatonin levels. iii. Low energy or fatigue.
Quetiapine (Seroquel) is an SGA medication that antago- iv. Low self-esteem.
nizes histamine, dopamine D2, and serotonin 5HT2 recep- v. Poor concentration or difficulty making decision.
tors. At low doses, the medications main effect is as an vi. Feelings of hopelessness.
antihistamine. Therefore, it can be used in low doses as a C. During the 2-year period of the disturbance, the person
hypnotic. Quetiapine is indicated for treatment of schizo- has never been without the symptoms in criterion A or
phrenia and bipolar disorder. As noted previously, quetiap- B for more than 2 months at a time.
ine has been used as a second medication (augmentation) in D. No major depressive episodes have been present the
treatment-resistant depression35 or as a single antidepressant first 2 years of the disturbance.
medication.36 Side effects of quetiapine include QT prolonga- E. There has never been a manic episode, mixed episode,
tion, weight gain, extrapyramidal symptoms, headache, lens or hypomanic episode and criteria have never been
changes/cataracts, and decreased white blood cell count. met for cyclothymic disorder.
Even at low doses, quetiapine has been associated with sig- Adapted from American Psychiatric Association: Diagnostic and Statistical
nificant weight gain. Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.

Dysthymic Disorder
Dysthymic disorder (Box 2912) is manifested by a
depressed mood for most of the day, for more days than
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not for at least 2 years. During depressed mood and two or
more of the following are present2:
1. Poor appetite or overeating.
2. Insomnia or hypersomnia.
3. Low energy or fatigue.
4. Low self-esteem.
5. Poor concentration or difficulty making decisions.
6. Feelings of hopelessness.
The diagnosis of dysthymic disorder is NOT made if
there has been an MDE during the 2-year period qualifying
for dysthymic disorder. In addition, an ME, a hypomanic
episode, or a mixed episode cannot have occurred
previously.
Cyclothymic Disorder The diagnostic criteria for cyclothymic
disorder (Box 2913) require that the patient have numerous
periods of both hypomania and depressive symptoms for 2
years that do not meet criteria for MDEs.2 The periods of
depressive or hypomanic symptoms can disturb sleep.
Bipolar Disorders
The bipolar disorders include bipolar I (BP-I) and bipolar II
(BP-II)2 (Box 2914). The major difference between these
disorders is that the up period in BP-II is hypomania and
the patient has never had an ME or mixed episode. A BP-I
patient can have hypomania or most recently be depressed
BUT the diagnosis of BP-I requires a current or previous
mixed episode or ME. The difference between mania and
BOX 2913
Diagnostic Criteria for Cyclothymic Disorder
A. For at least 2 years, the presence of numerous periods
with hypomanic symptoms and numerous periods of
depressive symptoms that do not meet criteria for major
depressive episodes. For children and adolescents, the
duration must be at least 1 year.
B. During the above 2-year period, the person has not
been without the symptoms of criterion A for more than
2 months at a time.
C. No major depressive episode, manic episode, or mixed
episode has been present during the first 2 years of the
disturbance.
D. The symptoms in criterion A are not better accounted
for by schizoaffective disorder and are not
superimposed on schizophreniform disorder, delusional
disorder, or psychotic disorder not otherwise classified.
E. Symptoms are not due to physical effects of a substance
or a general medical condition.
F. The symptoms cause clinical significant disorder or
impairment in social, occupation, or other important
areas.
Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.
Chapter 29 Psychiatry and Sleep 603
hypomania is one of degree of severity. Patients with mania
are severely impaired and are often hospitalized. Their
actions often cause financial or physical harm to themselves
or others.
In summary:
1. BP-I diagnosis requires:
A. A current (or recent) hypomanic episode, ME, mixed
episode, or MDE.
B. If the current episode is hypomanic or an MDE, there
must be history of a prior mixed episode or ME.
Note that, unlike diagnostic criteria for BP-II, the pres-
ence of at least one MDE is not required.
2. BP-II diagnosis requires at least one hypomanic episode,
one or more depressive episodes, and no history of current
(or prior) MEs or mixed episodes.
Bipolar Depression
The depression of BP disorders is problematic for several
reasons. First, treatment of depression in BP-I patients can
send the patient into mania unless they are on a mood sta-
bilizer. Second, there is a great risk of suicide during the
depressive phasea lifetime risk of suicide attempts up to
25%! Third, only a few medications are actually FDA
approved for bipolar depression. Some bipolar patients
present with complaints of depression and may be misdiag-
nosed as MDD (unipolar depression) rather than bipolar
depression. It is important to question patients carefully
about prior symptoms consistent with mania or hypomania.
There are no pathognomonic characteristics of BP-I depres-
sion compared with unipolar depression. Table 295 present
characteristics that are more probable in each category.42
Sleep in Bipolar Disorder
In BP-I, there is usually severe insomnia and a reduced need
for sleep during MEs or hypomanic episodes. BP-II patients
BOX 2914
Bipolar Disorders
BIPOLAR I DISORDER (AT LEAST ONE MANIC OR
MIXED EPISODE)
A. Currently (or recently) hypomanic, manic, mixed, or
major depressive episode.
B. If current episode is hypomanic or major depressive
episode, there has previously been at least one manic or
mixed episode.
BIPOLAR II DISORDER (AT LEAST ONE HYPOMANIC
EPISODE, NO MANIC, NO MIXED)
A. Presence (or history) of one or more major depressive
episodes.
B. Presence (or history) of at least one hypomanic episode.
C. There has never been a manic or mixed episode.
Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.
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TABLE 295
Manifestations of Patients with Bipolar and
Unipolar Depression
BIPOLAR I DEPRESSION UNIPOLAR DEPRESSION
MORE LIKELY MORE LIKELY
Hypersomnia Prominent insomnia
Hyperphagia Reduced appetite, weight
Psychomotor retardation loss
Earlier age of onset of Normal activity levels
first episode Later age of onset of first
Psychotic features episode
(pathologic guilt) Somatic complaints
Lability of mood No family history of bipolar
Family history of bipolar
disorder
From Mitchell PB, Goodwin GM, Johnson GF, Hirschfeld RMA: Diagnostic
guidelines for bipolar depression: a probabilistic approach. Bipolar Disord
2008;10:144152.
do not have full-blown mania; they are less likely to present
with episodes of severely short sleep duration. However,
insomnia can still be a significant problem. During bipolar
depression, hypersomnia complaints are often more
prominent than insomnia complaints. However, insomnia
can also be a significant problem in these patients as well.
Adequate treatment of the mania and depression in patients
with bipolar disorders is essential to improve sleep in these
patients. Specific treatments for insomnia in bipolar patients
would include use of BZRA hypnotics, ramelteon, loraze-
pam, clonazepam, and sedating SGAs (Seroquel). One would
not use sedating antidepressants (at least at an antidepressant
dose) in BP-I patients to avoid the precipitation of mania.
Genetics in Mood Disorders
Genetic factors account for 33% of the risk of major depres-
sion and more than 85% of the risk of bipolar disorder.43
Treatment of Bipolar Disorders
The treatment of bipolar disorders is complex.44,45 A brief
overview follows. Most sleep physicians who are not psychia-
trists will probably not be the primary physician treating a
patient for bipolar disorder. However, an understanding of
the approach is important. A well-known treatment algo-
rithm, the Texas Implementation of Medical Algorithm
(TIMA) for bipolar disorder, may be found at http://
www.dshs.state.tx.us/mhprograms/pdf/TIMABDalgos
2005.pdf
Other treatment guidelines are available.46,47 The treat-
ment of bipolar disorders is usually grouped into three treat-
ment phases: acute bipolar mania/mixed, bipolar depression,
and bipolar maintenance (Box 2915). The medications FDA
approved for the different treatment phases are listed in
Table 296. The major medication groups used include
mood stabilizers and atypical antipsychotics. Antidepres-
sants can be used for BP-I depression but usually only after
several other medications have failed and always in combi-
nation with an antimanic medication (mood stabilizer). In
BOX 2915
Bipolar Disorder ITreatment Phases and Goals
Mania/mixed
Rapid onset of action
Relief of symptoms
No depression induction
Typical treatments: divalproex, SGA, or a combination
Bipolar depression
Relief of symptoms
No mania induction
Typical treatments: antimanic medication (lithium or
divalproex) + lamotrigine, quetiapine XR, or a
combination of olanzapine and fluoxetine
Maintenance
Prevention of relapse into mania or depression
Reduction of co-morbid anxiety
Typical treatments: lithium, divalproex, lithium +
lamotrigine; aripiprazole or ziprasidone frequently
added in patients with frequent relapse
SGA = second-generation antipsychotic (aripiprazole, olanzapine,
quetiapine).
BP-II patients who have not displayed a manic episode over
many years of depressive episodes, some clinicians will use
an antidepressant without a mood stabilizer.
Acute Mania The newer atypical antipsychotic drugs such as
risperidone (Risperdal), quetiapine (Seroquel), aripiprazole
(Abilify), ziprasidone (Geodon), and olanzapine (Zyprexa)
are often used in acutely manic patients because these medi-
cations have a rapid onset of psychomotor inhibition, which
may be life-saving in the case of a violent or psychotic
patient. These medications are approved for use in acute
mania, alone or in combination with lithium or divalproex.
The approved mood stabilizers for mania include lithium,
divalproex (Depakote), and carbamazepine (Tegretol).
Divalproex (Depakote) is an enteric-coated formulation of
sodium valproate and valproic acid in a 1 : 1 molar ratio.
Valproic acid (Depakene) and injectable sodium valproate
(Depacon) are other available formulations. Divalproex is
available in a long-acting preparation (Depakote ER), allow-
ing once-daily dosing. The combination of an atypical anti-
psychotic and a mood stabilizer is also often used for severe
mania. Lithium must be titrated up slowly and is not the
drug of choice for acute severe mania. Antimania effects
occur after 1 to 3 weeks of lithium at therapeutic doses. If
lithium is used for acute mania, it usually requires the addi-
tion of another medication. Lithium side effects are experi-
enced by up to 30% of patients taking this medication and
include tremor, nausea, weight gain, fatigue, and mild cogni-
tive impairment. A number of medications have important
drug interactions with lithium. For example, diuretics and
nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce
renal clearance (increase lithium levels). Divalproex is prob-
ably the mood stabilizer of choice for acute mania in
this situation because it can be titrated up fairly rapidly
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TABLE 296
U.S. Food and Drug AdministrationApproved Medications for Bipolar Disorder
GENERIC TRADE
Valproic acid/valproate Depakote
Carbamazepam ER Equetro
Lamotrigine Lamictal
Lithium
Aripiprazole Abilify
Ziprasidone Geodon
Risperidone Risperdal
Quetiapine XR Seroquel
Olanzapine Zyprexia
Olanzapine + fluoxetine Symbyax
*Approved for maintenance as adjunctive treatment with lithium or divalproex.
Approved for combination with lithium or valproic acid.
BP-I, BP-II = bipolar I and II; FDA = U.S. Food and Drug Administration; NFA = not FDA approved for this indication but often used.
(2030 mg/kg/day on a tid schedule). In less urgent cases,
the medication is started at 250 mg with a meal on day 1,
then increased to 250 mg tid for 3 to 6 days. Mania typically
begins improving 1 to 4 days after drug levels exceed 50 g/
mL. Side effects of divalproex include nausea, vomiting, dys-
pepsia, and diarrhea. When titrated up rapidly, divalproex
can also cause sedation. Rare but very severe side effects
include hepatoxicity, leukopenia, thrombocytopenia, and
pancreatitis. Drug levels can be obtained before the morning
dose with a therapeutic range of 50 to 125 g/mL (com-
monly felt > 75 needed for mania). Both lithium and dival-
proex have been associated with an increased risk of birth
defects. Of note, lithium increases stage N3 sleep and
decreases REM sleep.
Mixed Episode The treatment of a mixed episode is similar to
the treatment of mania.
Maintenance Treatment The goal of maintenance treatment is
to prevent relapse of mania and depressive episodes. The
cumulative rate of relapse after an episode of mania in the
absence of maintenance treatment is 50% at 12 months
and nearly 90% at 60 months. Lithium and lamotrigene are
the two mood stabilizers that are FDA approved for mainte-
nance treatment. Divalproex is not FDA approved for main-
tenance treatment but is also widely used for this application.
Lithium has the advantage of also preventing bipolar depres-
sion and reducing suicide risk. It appears to have an advan-
tage over divalproex in these respects. Lamotrigine (Lamictal)
may be used as a mood stabilizer for maintenance. Lamotrig-
ine also has antidepressant effects and, therefore, is useful for
maintenance. This medication requires a slow upward titra-
tion (over 6 wk) to avoid a significant skin rash. It can be
associated with the Stevens-Johnson syndrome. Lamotrigine
is NOT approved for acute mania. Aripiprazole (Abilify) and
Chapter 29 Psychiatry and Sleep 605
MANIA MIXED MAINTENANCE DEPRESSION
X X NFA NFA
X X
X (BP-I) NFA
X X X NFA
X X X
X X X
X X
X X X* X (BP-I and BP-II)
X X X
X (BP-I)
ziprasidone (Geodone) are the only antipsychotic medica-
tions currently approved for maintenance. Aripiprazole is a
partial dopamine D2 agonist and serotonin 5HT1A agonist
as well as an antagonist at 5HT2A receptors. Ziprasidone
antagonizes dopamine D2 receptors and serotonin 5HT2
receptors. Of note, even with maintenance treatment relapse
of mania or depression may occur in up to 30 to 40% of
BP-I patients in the first year and up to 75% over five years.
Bipolar Depression Treatment of bipolar depression is often
challenging.47 Few medications are actually FDA approved
for treatment of bipolar depression. Quetiapine XR or a com-
bination of olanzapine and FLX (Symbyax) are the only
medications FDA approved for bipolar depression. One
problem with the olanzapine/FLX combination is that FLX
has a very long half-life. If mania occurs, the residual effects
can be problematic.
Studies have NOT documented an advantage of the
addition of a standard antidepressant to a mood stabilizer
in treatment of bipolar depression.48 The addition of an
antidepressant can worsen anxiety, increase mood insta-
bility, or trigger a switch to mania. However, individual
patients may benefit from the long-term combination of a
mood stabilizer and an antidepressant. If an antidepressant
is used, the activating ones like venlafaxine or duloxetine are
more likely to cause switches (mania). Bupropion or a non-
fluoxetine SSRI are used by many clinicians.
Although not FDA approved for bipolar depression, most
treatment algorithms (Fig. 293) use a mood stabilizer
(lithium or divalproex) as the initial step. Lithium is gener-
ally more effective for bipolar depression than divalproex.
Many clinicians would next add lamotrigine, which has anti-
depressant activity. If this was not successful, quetiapine or
the olanzapine/FLX combination could be added. If this does
not work, antidepressants are then often added.
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606 Chapter 29 Psychiatry and Sleep

ALGORITHM FOR THE TREATMENT OF

Antimanic  Li, valproex
BIPOLAR DISORDER ICURRENTLY DEPRESSED
Li  lithium
On Li On other antimanic On no antimanic, On no antimanic, LTG  lamotrigine
with history of without history of
severe and/or severe and/or QTP  quetiapine
Increase to  .8 (continue) recent mania recent mania OFC  olanzapine  fluoxetine
combination
CONT  continue
Stage 1 Antimanic  LTG LTG

Response
CONT
Partial response
or nonresponse

Stage 2 QTP* or OFC*

Response
CONT
Partial response
or nonresponse

Combination from Li, LTG,

Stage 3
QTP or OFC

Response
CONT
Partial response
or nonresponse

FIGURE 293 The first three stages of a five-stage algorithm for treatment of bipolar depression (Bipolar Disorder ICurrently Depressed). Stage 1 consists
of an antimanic medication (lithium or divalproex) and lamotrigine. Stage 2 consists of either quetiapine or the olanzapine + fluoxetine combination used
alone. *There is overlap with the medications in Stage 1. The stage 1 medications are gradually withdrawn. QTP or OFC used alone after taper of stage 1
medications (if taper possible). Stage 3 means a combination of a medication used in stage 2 and one or more medications used in stage 1. For example:
Lithium + lamotrigine + quetiapine. From Texas Implementation of Medication Algorithm for Bipolar Disorders. Austin: Texas Department of State Health
Services, 2005.

TABLE 297 of the following symptoms developed abruptly and reached

Anxiety Disorders a peak within 10 minutes: palpitation, pounding heart, or
Panic disorder with Acute stress disorder accelerated heart rate; sweating; trembling or shaking; sensa-
agoraphobia Generalized anxiety tion of shortness of breath or smothering; feeling of choking,
Panic disorder without disorder chest pain or distress; nausea or abdominal discomfort;
agoraphobia Anxiety disorder due to a feeling dizzy, unsteady, lightheaded, or faint; derealization
Agoraphobia without general medical condition (feelings of unreality) or depersonalization (being detached
panic disorder Substance-induced from oneself); fear of losing control or going crazy; fear of
Specific phobia anxiety disorder dying; paresthesias (numbness or tingling sensation); and
Obsessive compulsive Anxiety disorderNOS chills or hot flashes. Panic attacks can occur at night (noc-
disorder Social phobia turnal panic). Patients usually (but not always) have a
Posttraumatic stress
history of panic attacks during the day (see Box 2916).
disorder
NOS = not otherwise specified.
Adapted from American Psychiatric Association: Diagnostic and Statistical
Panic Disorder
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Panic disorder is characterized by patients who have recur-
Association, 2000. rent panic attacks, OR if only one panic attack has occurred,
the attack has been followed by 1 month (or more) of the
following: persistent concern about having additional attacks,
ANXIETY DISORDERS
worry about the implications of the attack or its conse-
Table 297 is a list of anxiety disorders. quences, or a significant change in behavior related to the
attacks (Box 2917). The attacks are not due to a substance,
medication, or general medication condition.2,49 Note that
Panic Disorder
the DSM-IV has classifications of panic disorder with or
Panic Attack without agoraphobia, as well as agoraphobia. Agoraphobia is
A panic attack (Box 2916) is characterized2 by a discrete fear of being in a place that is unfamiliar or for which there
period of intense fear or discomfort in which four (or more) is no easy escape or which they have no familiarity. The fear
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could be having a panic attack and not being able to escape
and being embarrassed. Agoraphobia without panic attack is
a separate disorder. Patients with this disorder have agora-
phobia, but it is not tied to apprehension about a panic attack
but to apprehension about being in a strange place or being
out in the open or near crowds (social anxiety) (Boxes 2917
and 2918).
BOX 2916
Criteria for Panic Attack
A. A discrete period of intense fear or discomfort in which
four (or more) of the following symptoms developed
abruptly and reached a peak within 10 minutes:
i. Palpitation, pounding heart, or accelerated heart
rate
ii. Sweating
iii. Trembling or shaking
iv. Sensation of shortness of breath or smothering
v. Feeling of choking
vi. Chest pain or distress
vii. Nausea or abdominal discomfort
viii. Feeling dizzy, unsteady, lightheaded, or faint
ix. Derealization (feelings of unreality) or
depersonalization (being detached from oneself )
x. Fear of losing control or going crazy
xi. Fear of dying
xii. Paresthesias (numbness of tingling sensation)
xiii. Chills or hot flashes
Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.
BOX 2917
Criteria for Diagnosis of Panic Disorder
A. Both (i) and (ii) are present
i. Recurrent unexpected panic attacks.
ii. At least one of the attacks has been followed by 1
month (or more) of the following:
a. Persistent concern about having additional attacks.
b. Worry about the implications of the attack or its
consequences (e.g., losing control, having a heart
attack, going crazy).
c. A significant change in behavior related to the
attacks.
B. The panic attacks are not due to the direct physiologic
effects of a substance (e.g., a drug of abuse, medication)
or a general medical condition (e.g., hyperthyroidism).
C. The panic attacks are not better accounted for by
another mental disorder (e.g., social phobia, specific
phobias, obsessive-compulsive disorder, PSTD, or
separation anxiety disorder).
PTSD = posttraumatic stress disorder.
Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.
Chapter 29 Psychiatry and Sleep 607
Sleep and Panic Disorder A nocturnal panic attack is in the
differential diagnosis of parasomnias including night terrors.
The majority of patients with panic disorder have at least
one nocturnal panic attack. About one third of patients with
panic disorder have recurrent nocturnal panic attacks. Of
those panic disorder patients with nocturnal panic attacks,
up to two thirds report insomnia often associated with fear
of returning to sleep.49 The symptom of dyspnea appears to
be more common in nocturnal panic attacks. The attacks
occur from nonrapid eye movement (NREM) sleep, com-
monly at the transition from stage N2 to stage N3 sleep. In
most patients, sleep architecture is normal (normal REM
latency and sleep efficiency). However, some patients may
develop sleep phobiaand this can be associated with find-
ings consistent with insomnia (Box 2919).
Differential Diagnosis of Panic Attack The differential diagnosis
of panic attacks includes night terrors, nightmares, posttrau-
matic stress disorder (PTSD), and REM behavior disorder.
BOX 2918
Sleep and Panic Disorder
Most patients with nocturnal panic attacks also have
daytime panic attacks.
Majority of patients with panic disorder have at least one
nocturnal panic attack.
One third or more of patients have recurrent nocturnal
panic attacks.
Usually during NREM sleep at transition to stage N3.
Two thirds of patients with panic disorder report
sleep-onset and sleep-maintenance insomnia (fear of
returning to sleep).
In contrast to a NREM parasomnia, the patient is awake.
In contrast to nightmares, there is no dream recall.
If SSRIs are started, they should be started at low doses to
avoid exacerbation of nocturnal panic.
NREM = nonrapid eye movement; SSRIs = selective serotonin reuptake
inhibitors.
BOX 2919
Differential Diagnosis of Nocturnal Panic Attacks
1. Medical disorder (hyperthyroidism, pheochromocytoma)
2. Paroxysmal nocturnal dyspnea (CHF)
3. Arousal from OSA
4. Arousal for GERD
5. Nocturnal laryngospasm
6. NREM parasomnianight terrors
7. PTSD
8. RBD
CHF = congestive heart failure; GERD = gastroesophageal reflux disease;
NREM = nonrapid eye movement; OSA = obstructive sleep apnea;
PTSD = posttraumatic stress disorder; RBD = rapid eye movement sleep
behavior disorder.
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608 Chapter 29 Psychiatry and Sleep
Night terrors usually begin in childhood and during the
episodes the individual is not well aware of his or her sur-
roundings and does not remember the episodes in the
morning. In panic attacks, the patient is awake and aware of
his or her surroundings. In nightmares, the patient usually
is aware of a frightening dream. In contrast, patients with
panic attacks remember the episode, but typically do not
report a terrifying dream. In nocturnal laryngospasm, the
patient wakes up choking with near-total cessation for
airflow from 5 to 43 seconds with stridor.
Treatment of Panic Disorder The treatment of panic attacks
includes behavioral psychotherapy or relaxation techniques
and pharmacotherapy.49,50 Although benzodiazepines (e.g.,
alprazolam, clonazepam) were the classic treatments for
panic disorder, the long-term treatment of the panic disorder
is an antidepressant. Both SSRIs (e.g., paroxetine, sertraline)
and TCAs (e.g., imipramine) must be started at very low
doses or the panic attack initially may be exacerbated. For
example, paroxetine is started at 10 mg daily or imipramine
at 10 to 25 mg daily. The doses are slowly increased to 20 to
40 mg for paroxetine or 100 to 200 mg for imipramine, as
tolerated. Because improvements may take 4 to 6 weeks or
longer, many physicians add benzodiazepines during the
early course of therapy. Alprazolam (Xanax) has a short half-
life and many psychiatrists prefer to use clonazepam, which
has a long duration of action. This is especially true for
patients requiring antianxiety treatment during the day.
Unfortunately, clonazepam (long duration of action) can be
quite sedating in some patients. Alprazolam is available in
an extended action preparation (Xanax XR), which prevents
the need for repeated dosing.
Generalized Anxiety Disorder
Generalized anxiety disorder (GAD) is characterized by
excessive anxiety and worry (apprehensive expectation),
occurring more days than not for a period of at least 6
months, about a number of events or activities (Box 2920).
The individual finds it difficult to control the worry. The
anxiety and worry are with three (or more) of the following
six symptoms (with at least one symptom present for more
days than not for the past 6 mo)2,51: (1) restlessness or feeling
keyed up or on edge, (2) being easily fatigued, (3) difficulty
concentrating or mind going blank, (4) irritability, (5) muscle
tension, or (6) sleep disturbance (difficulty falling or staying
asleep or restless unsatisfying sleep).
Sleep in GAD
Chronic subjective sleep disturbance is common among
people with GAD. Few PSG results are available but usually
describe increased sleep latency and reduced sleep efficiency
and total sleep time, as well as sleep continuity disturbance
and reduced slow wave sleep. Fava and coworkers52 com-
pared the combination of extended-release zolpidem and
escitalopram versus placebo and escitalopram in a group of
patients with insomnia and co-morbid GAD. The group with
BOX 2920
Generalized Affective Disorder
Diagnostic Criteria
A. Excessive anxiety and worry (apprehensive expectation),
occurring more days than not for at least 6 months,
about a number of events or activities (such as work or
school performance).
B. The person finds it difficult to control the worry.
C. The anxiety and worry are associated with three (or
more) of the following six symptoms (with at least one
symptom present for more days than not for the past 6
months):
i. Restlessness or feeling keyed up or on edge.
ii. Being easily fatigued.
iii. Difficulty concentrating or mind going blank.
iv. Irritability.
v. Muscle tension.
vi. Sleep disturbance (difficulty falling or staying asleep
or restless unsatisfying sleep).
D. The focus of anxiety and worry is NOT confined to
features of an axis I disorder (i.e., another major
psychiatric disorder: e.g., worry about having a panic
attack, being embarrassed in public with social phobia,
being contaminated in obsessive compulsive disorder).
Adapted from American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric
Association, 2000.
the addition of zolpidem had improved insomnia (subjective
total sleep time) and next day symptoms (but not anxiety
symptoms). Note that zolpidem is a BZRA hypnotic without
antianxiety activity. Medications such as clonazepam and
lorazepam could be used for sleep in GAD patients for both
their hypnotic and their antianxiety effects. Alprazolam is
another alternative, although it may have less hypnotic activ-
ity because it tends to be less sedating. Note that clonazepam,
lorazepam, and alprazolam are not FDA approved for use as
hypnotics.
Differential Diagnosis of Sleep Problems with GAD In psychophys-
iologic insomnia, patients are anxious about their sleep but
not to the degree as in GAD, and in psychophysiologic
insomnia, the anxiety is focused on sleep. Other anxiety
disorders such as phobia, or anxiety about medical condi-
tions, or substance use anxiety should be considered.
Treatment of GAD Treatment includes psychotherapy, benzo-
diazepines (alprazolam [Xanax], lorazepam [Ativan], diaz-
epam [Valium], clonazepam [Klonopin]), and SSRI/SNRIs.
The medications with demonstrated effectiveness include
citalopram (Celexa), escitalopram (Lexapro), paroxetine
(Paxil), and sertraline (Zoloft).51,53 Some patients may
feel more anxious when starting an SSRI, and benzodiaze-
pines can be used during the first 4 to 6 weeks of treatment.
A discontinuation syndrome has been described with
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alprazolam after only 6 to 8 weeks of treatment. In general,
all benzodiazepines should be weaned rather than abruptly
discontinued.
Posttraumatic Stress Disorder
PTSD2 is a disorder of symptoms (Box 2921) that
occur after exposure to an extremely traumatic stressor
involving (1) direct personal experience of an event that
involves actual or threatened death, serious injury, or other
threat to ones physical integrity; (2) witnessing an event
that involves death, injury, or a threat to the physical integ-
rity of another person; or (3) learning about unexpected or
violent death, serious harm, or threat of death or injury
experienced by a family member or other close associate.
The persons response to the event must involve intense
fear, helplessness, or horror. The characteristic symptoms
resulting from the exposure to the extreme trauma include
persistent re-experiencing of the traumatic event, persistent
avoidance of stimuli associated with the trauma and numbing
of general responsiveness, and persistent symptoms of
increased arousal.
BOX 2921
Posttraumatic Stress DisorderDiagnostic Criteria
A. The person has been exposed to a traumatic event in
which both of the following were present:
i. The person experienced, witnessed, or was confronted
with an event or events that involved actual or
threatened death or serious injury, or a threat to the
physical integrity of self or others.
ii. The persons response involved intense fear,
helplessness, or horror.
Note: In children, this may be expressed instead by
disorganized or agitated behavior.
B. The traumatic event is persistently re-experienced in one
(or more) of the following ways:
i. Recurrent and intrusive distressing recollections
of the event, including images, thoughts, or
perceptions.
Note: In young children, repetitive play may occur in
which themes or aspects of the trauma are expressed.
ii. Recurrent distressing dreams of the event.
Note: In children, there may be frightening dreams
without recognizable content.
iii. Acting or feeling as if the traumatic event were
recurring (includes a sense of reliving the experience,
illusions, hallucinations, and dissociative flashback
episodes, including those that occur on awakening or
when intoxicated).
Note: In young children, trauma-specific reenactment
may occur.
iv. Intense psychological distress at exposure to internal
or external cues that symbolize or resemble an aspect
of the traumatic event.
Adapted from American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association, 2000.
Chapter 29 Psychiatry and Sleep 609
Associated Features
Recurrent distressing dreams (i.e., nightmares) of the
traumatic event are one of the diagnostic features of
PTSD. For many patients with PTSD, the associated
nightmares represent one of the most frequently occur-
ring and problematic aspects of the disorder. Persistent
nightmares may also be one of the most enduring symptoms
in PTSD (see Treatment of Nightmares in PTSD). High
percentages of patients (7090%) describe subjective sleep
disturbance. However, PSG studies of patients with PTSD
have yielded variable and inconclusive findings5456 in regard
to abnormalities in REM sleep, and controlled studies have
not found consistent abnormalities with sleep architecture.
Increased rates of sleep-related breathing disturbance have
been reported in trauma victims.
Symptoms of PTSD can begin immediately after the event
or have a delayed onset (up to years later). Patients with
PTSD also report a heightened startle response. Given a
common exposure to a traumatic event, PTSD appears to
occur more frequently in women than in men. Patients
with PTSD also may have depression and may abuse ethanol
or other substances.
v. Physiologic reactivity on exposure to internal or
external cues that symbolize or resemble an aspect of
the traumatic event.
C. Persistent avoidance of stimuli associated with the trauma
and numbing of general responsiveness (not present
before the trauma), as indicated by three (or more) of the
following:
i. Efforts to avoid thoughts, feelings, or conversation
associated with the trauma.
ii. Efforts to avoid activities, places, or people that arouse
recollection of the trauma.
iii. Inability to recall important aspects of the trauma.
iv. Markedly diminished interest or participation in
significant activities.
v. Feeling of detachment or estrangement from others.
vi. Restrict range of affect (e.g., inability to have loving
feelings).
vii. Sense of foreshortened future (e.g., does not expect to
have a career, marriage, children, or a normal lifespan).
D. Persistent symptoms of increased arousal (not present
before the trauma) as indicated by two or more of the
following:
i. Difficulty falling or staying asleep.
ii. Irritability or outbursts of anger.
iii. Difficulty concentrating.
iv. Hypervigilance.
v. Excessive startle response.
E. Duration of the disturbance (symptoms in criteria B, C,
and D) is more than 1 month.
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610 Chapter 29 Psychiatry and Sleep
Differential Diagnosis of Nocturnal Event Due to PTSD
The differential of awakening with anxiety includes sleep
panic disorder, REM sleep behavior disorder, and night
terrors. Unlike patients with panic attacks during sleep,
patients with PTSD can recount a dream of a specific trau-
matic event. In contrast to night terrors, patients become
alert quickly after awakening. Sleep studies in patients with
PTSD have produced conflicting results. The duration of
REM latency and the amount of REM sleep have varied
among studies. This may be a reflection of the fact that some
patients with PTSD are also suffering from depression.
Several studies have found an increase in REM density in
patients with PTSD (as in depression), an increase in body
movements during sleep, and the presence of periodic limb
movements in sleep (PLMS).54,56 Some patients may have
REM sleep without atonia, but some are already on SSRIs
that can cause this finding.
Treatment of PTSDGeneral Considerations
The treatment of PTSD includes counseling and medication.
Although many patients with PTSD have anxiety, ben-
zodiazepines have not been effective, and withdrawal of
these medications may produce a flair of symptoms.57 Ser-
traline and paroxetine are the only antidepressants FDA
approved for treatment of PTSD. However, other SSRIs
may also be effective. Sertraline was shown to be effective in
a double-blind, placebo-controlled study.58 Open-label trials
of paroxetine59 and escitalopram60 in PTSD have also been
published.
Treatment of Nightmares in PTSD
As noted previously, recurrent disturbing nightmares may
be an important problem in PTSD and do not always
respond to general PTSD treatments. Cognitive behavioral
treatments have been used to treat nightmares with some
success. One behavior technique called imagery rehearsal
therapy has proved successful in several studies.61 Patients
are asked to rewrite their previous dreams with a positive
outcome. In the past, use of medications for nightmares had
limited success. Recently, several small studies report success
with the alpha 1 blocker prazosin.62,63 Note that when pra-
zosin is started, the drug should be initiated with a dose of
1 mg at bedtime to avoid severe first-dose hypotension
(often orthostatic hypotension). The drug can then be
titrated upward slowly over several nights. A parallel
placebo-controlled study in trauma nightmares in PTSD
due to combat showed improvements in sleep and reduction
in nightmares with prazosin. A relatively high dose (mean
13 mg) was reached over a protracted period of upward
titration.62 Another study using a cross-over design and a
dose of 2 to 6 mg at bedtime also found benefit in civilian
trauma PTSD.63 One study also reported success in reducing
disturbing nightmares using topiramate in PTSD patients.64
However, neither prazosin nor topiramate is FDA approved
for treatment of nightmares in PTSD.
CLINICAL REVIEW QUESTIONS
1. Which of the following is true about MDEs?
A. Insomnia complaints in 80% of patients.
B. Hypersomnia complaints in about 50% of patients.
C. Hypersomnia complaints in 60% of patients.
D. Insomnia complaints in 40% of patients.
2. Which of the following is a common PSG finding during
MDE?
A. Short sleep latency.
B. Short REM latency.
C. Increased total sleep time.
D. Increased REM sleep in the last part of the night.
E. Decreased REM density.
3. The most common misdiagnosis in bipolar depression is:
A. Anxiety disorder.
B. Substance abuse.
C. Personality disorder.
D. Unipolar depression.
4. Treatment of bipolar depression in BP-I patients with
antidepressants may lead to:
A. Anxiety.
B. Greater mood instability.
C. Mania induction.
D. B and C.
E. A, B, and C.
5. The family of a 50-year-old man reports a recent change
in his behavior. He has been sleeping 5 hours per night
but seems well rested. The patient never stops talking
and switches from one topic to another. He starts many
new projects that he never completes. The patient has
continued to work and manage his home responsibilities.
He had an episode of depression about a year ago. What
is the best description of the behavior?
A. BP-I.
B. BP-II
C. MDD.
D. Cyclothymic in up phase.
6. Which of the following would be more typical for bipolar
depression than for unipolar depression?
A. Loss of appetite.
B. Hypersomnia.
C. Normal activity.
D. No family history of bipolar disorder.
7. During a PSG, a patient suddenly arouses from stage N2
and sits up in bed and appears awake. He does not return
to sleep and develops tachycardia. He signals for the tech-
nologist, who comes to evaluate him. The patient is trem-
bling and sweaty but completely alert and responsive. He
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reports feeling that he is about to die. What is the most
likely diagnosis?
A. Confusional arousal.
B. Nocturnal frontal lobe epilepsy.
C. Panic attack.
D. Sleep terror.
Answers
1. A. MDE is characterized by complaints of insomnia in a
majority of patients.
2. B. PSG in MDE shows short REM latency, long sleep
latency, decreased total sleep time, more REM sleep in the
first part of the night.
3. D. Unipolar depression is often diagnosed because a
history for prior mania or hypomania was not sought by
the treating clinician.
4. E. Treatment with antidepressant (especially without a
mood stabilizer) can cause mania, mood instability, and
anxiety.
5. B. The patient is able to work and is not disabled, but
there has been a significant acute change in his behavior.
There is a history of previous depression. The best diag-
nosis based on current knowledge is BP-II based on the
current hypomanic episode.
6. B. Hypersomnia can occur with unipolar MDD but is
more typical of bipolar depression.
7. C. Panic attack. Panic attacks occur during established
wake (including after arousal from sleep) with manifesta-
tions of pounding heart, diaphoresis and often chest pain
or choking.
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 Appendix 29-1

Patient Health Questionnaire (PHQ-9)

Over the last 2 weeks, how often have you been bothered by
any of the following problems? NOT SEVERAL MORE THAN NEARLY
Put an X in the box that indicates your answer. AT ALL DAYS HALF THE DAYS EVERY DAY
1. Little interest or pleasure in doing things. 0 1 2 3
2. Feeling down, depressed, or hopeless. 0 1 2 3
3. Trouble falling or staying asleep or sleeping too much. 0 1 2 3
4. Feeling tired or having little energy. 0 1 2 3
5. Poor appetite or overeating. 0 1 2 3
6. Feeling bad about yourself or that you are a failure or 0 1 2 3
have let yourself or your family down.
7. Trouble concentrating on things, such as reading the 0 1 2 3
newspaper or watching television.
8. Moving or speaking so slowly that other people could 0 1 2 3
have noticed. Or the oppositebeing so fidgety or restless
that you have been moving around a lot more than usual.
9. Thoughts that you would be better off dead or of hurting 0 1 2 3
yourself in some way.
10. If you checked off any problems, how difficult have these Not at Somewhat Very difficult Extremely
problems made it for you to do your work, take care of all difficult difficult
things at home, or get along with other people?
14 minimal depression, 59 mild depression, 1014 moderate depression, 1519 moderately severe depression, 2027
severe depression.

PHQ-9 is adapted from PrimeMD today, developed by Dr. RL Spitzer, JBW Williams, K Kroenke, and colleagues, with an education grant from Pfizer,
Inc. Use of the PHQ-9 may only be made in accordance with the terms of use available at http://www.pfizer.com
Copyright 1999 Pfizer, Inc.
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Sleep and Nonrespiratory
PhysiologyImpact on Selected
Medical Disorders
Chapter Points
The secretion of GH and PRL by the pituitary is
controlled mainly by the timing of sleep. GH secretion
in men is tightly tied to the first cycle of stage N3
sleep. PRL secretion is increased during sleep
(inhibited by wakefulness).
The secretion of ACTH, cortisol, and TSH are mainly
controlled by circadian timing (time of day) influences
with weaker sleep-related effects. The secretion of
ACTH and cortisol peaks soon after awakening. TSH
secretion is under circadian control (peaks during the
night). Sleep inhibits TSH secretion.
Ghrelin is a hormone secreted by the stomach that
stimulates the appetite and is increased by sleep loss.
Leptin is a hormone secreted by adipose tissue that
increases satiety. Leptin is decreased by sleep loss.
Studies suggest that individuals with decreased total
sleep time have an increased risk of developing
obesity.
The normal defense mechanisms to minimize the
detrimental effects of GER are not present during
sleep. Saliva secretion virtually stops and reflex
swallowing to clear refluxed material is not present.
This results in a prolonged ACT. The absence of
symptoms does not eliminate the presence of GER.
Esophageal pH monitoring often shows significant GER
episodes in asymptomatic patients.
Nocturnal GER is common in patients with OSA and is
improved with CPAP treatment.
Alpha-delta sleep (alpha anomaly) is not specific to
fibromyalgia. Alpha anomaly may be seen in
psychiatric disorders, in many chronic pain syndromes,
and in normal individuals.
Sleep in patients with the FS is abnormal and studies
have shown decreased total sleep time, increased
arousals, and decreased stage N3 and REM sleep. At
least in some patients, a poor night of sleep is
associated with worse daytime symptoms.
Chapter 30
This chapter reviews aspects of endocrine, gastrointestinal,
rheumatologic, and renal physiology and related medical
disorders relevant to sleep medicine. It is not a comprehen-
sive review of any area.
ENDOCRINE PHYSIOLOGY AND SLEEP
The timing of the secretion of important hormones with
respect to sleep and circadian control is briefly reviewed. The
secretion of some hormones is tied to sleep, whereas others
are under circadian control. A common strategy to deter-
mine whether sleep or circadian influence predominates is
to move the timing of sleep and determine what happens to
the pattern of hormone secretion.
GROWTH HORMONE
Growth hormone (GH) is secreted by somatotroph cells of
the anterior pituitary under hypothalamic control. GH
secretion is increased by GHRH (growth hormonereleasing
hormone) and decreased by somatostatin, both secreted by
the hypothalamus. GH secretion is also increased by acylated
ghrelin (ghrelin is secreted by the stomach). The most reli-
able burst of GH secretion is associated with the first slow
wave sleep (stage N3) cycle (any time of the day).1,2 This
is associated with increased GHRH and decreased
somatostatin.
In healthy adults, the 24-hour profile of plasma GH
consists of stable low levels abruptly interrupted by bursts
of secretion (Box 301 and Fig. 301). The most reproduc-
ible GH pulse occurs shortly after sleep onset. In men, the
sleep-onset GH pulse is the largest and often the only secre-
tory pulse over the 24-hour day. In women, daytime GH
pulses are more frequent and the sleep-onset pulse does
not account for the majority of the 24-hour secretory output
(Fig. 302). The amount of GH released is proportional to
slow wave activity. Figure 301 shows a large burst of GH
secretion after sleep onset. During the next nighttime period,
the subject is awake and there is only a slight increase in
GH secretion. The subject is allowed to sleep at 11 AM,
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616 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders

FIGURE 301 Mean 24-hour profile of plasma growth 20

hormone (GH) during a 53-hour period including 8 hours of
nocturnal sleep (dark blue bar), 28 hours of continuous 15

hormone (g/L)
Plasma growth
wakefulness (nocturnal hours: white bar), and 8 hours of
daytime sleep (light blue bar). Subjects were young healthy
10
men. The shaded area corresponds to normal 24-hour
conditions. The vertical bar at each time point represents the
standard error of the mean (SEM). The temporal organization 5
of GH secretion is mainly regulated by the homeostatic
control of sleep such that shifted sleep is associated with a 0
18 22 02 06 10 14 18 22 02 06 10 14 18 22
shift in the secretion of GH. Adapted from Van Cauter E,
Spiegel K: Circadian and sleep control of hormones. In Turek FW, Nocturnal sleep
Zee PC (eds): Regulation of Sleep and Circadian Rhythms. New Nocturnal sleep deprivation
York: Marcel Dekker, 1999, p. 399, with permission. Daytime sleep

MEN WOMEN
14 14

12 12
Plasma GH (g/L)

Plasma GH (g/L)
10 10

8 8

6 6

4 4

2 2

0 0
11 15 19 23 03 07 11 11 15 19 23 03 07 11

FIGURE 302 Growth hormone (GH) secretion in a group of young men (left) and women (right). The plots are mean values. The dark blue bar is the sleep
period. Men have most of their GH secretion during sleep, but in women, bursts during the day are more common. From Van Cauter E, Plat L, Copinschi G:
Interrelations between sleep and the somatotropic axis. Sleep 1998;21:553566.

BOX 301 normal sleep (slight increase in GH secretion occurs at night

Growth Hormone and Sleep even when individuals are awake) likely due to a decrease in
somatostatin. Of interest, ghrelin is also highest at night
Mensleep-onset GH pulse is generally the largest, and (peaks during first part of the night) and could contribute to
often the only, secretory pulse observed over the 24-hour the weak circadian component to control of GH release. An
span.
acyl chain (octanoate residue) is added to ghrelin by the
Womendaytime GH pulses are more frequent, and the
enzyme ghrelin-O-acyltransferase before it can bind GH
sleep-associated pulse, although still present, in the vast
secretagogue receptors. It is not known whether acetylated
majority of individual profiles does not account for the
majority of the 24-hour secretory output. ghrelin increases at night.
GH secretion is tied to sleep onset (start of stage N3
sleep) rather than time of day. GHRH and GHEffects on Sleep
Amount of GH secretion correlates with duration of stage
N3 episodes. Injections of GHRH stimulate stage N3 and slow wave activ-
GH = growth hormone. ity (electroencephalogram [EEG] spectral power in the delta
range). In contrast, injections of GH appear to enhance rapid
eye movement (REM) sleep, particularly in rodents.3 Soma-
and sleep onset is followed by a large burst in GH tostatin injections impair sleep quality in older, but not in
secretion. young, adult humans.4

Etiology of Sleep-Related GH Burst Changes in GH Secretion with Age

The sleep-related burst of GH secretion is due to increased The nocturnal increase in GH decreases with age in parallel
GHRH activity during stage N3 and decreased somatostatin. with the amount of stage N3 (formerly termed stages 3 + 4;
There is a circadian (time of day) peak in GH at the time of Fig. 303).5
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 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders 617

SLOW-WAVE SLEEP NOCTURNAL GROWTH HORMONE

200 1000

160 800

Amount secreted (g)

Minutes of III  IV

120 600

80 400

40 200

0 0

10 20 30 40 50 60 70 80 90 10 20 30 40 50 60 70 80 90
Age (years) Age (years)

FIGURE 303 Patterns of the amount of slow wave sleep (stage N3, formerly stages III + IV) and nocturnal GH secretion throughout aging, obtained in 102 healthy
nonobese men, ages 18 to 83 years, who were grouped according to age bracket (mean SEM for each age bracket). GH decreases with age in parallel to the amount of
slow wave sleep. Data from Van Cauter E, Plat L, Copinschi G: Interrelations between sleep and the somatotropic axis. Sleep 1998;21:553566.

20 FIGURE 304 Mean 24-hour profile of plasma cortisol

during a 53-hour period including 8 hours of nocturnal sleep
15 (dark blue bar), 28 hours of continuous wakefulness (nocturnal
cortisol (g/dL)

hours: white bar), and 8 hours of daytime sleep (light blue

Plasma

bar). Subjects were young healthy men. The shaded area

10
corresponds to normal 24-hour conditions. The vertical bar at
each time point represents the SEM. The plasma cortisol
5 remains largely synchronized to clock time even when sleep
is shifted, indicating a predominant role of circadian
0 rhythmicity in the control of hypothalamus-pituitary-adrenal
18 22 02 06 10 14 18 22 02 06 10 14 18 22
axis activity. Adapted from Van Cauter E, Spiegel K: Circadian
Nocturnal sleep and sleep control of hormones. In Turek FW, Zee PC (eds):
Nocturnal sleep deprivation Regulation of Sleep and Circadian Rhythms. New York: Marcel
Daytime sleep Dekker, 1999, p. 399, with permission.

SLEEP AND THE CORTICOTROPIC AXIS BOX 302

The adrenals secrete cortisol under the control of pituitary Adrenocorticotropic Hormone (ACTH) and Cortisol
adrenocorticotropic hormone (ACTH). There is strong cir- Under circadian control (peak around 7 AM).
cadian control of ACTH secretion (and cortisol). The Nadir shortly after the typical time of sleep onset (does
plasma levels of cortisol and ACTH peak in the early morning not depend on sleep).
and decline during the day (Box 302 and Fig. 304). The Peak levels in the early morning then decline over the
nadir of cortisol and ACTH levels is during the first part of day.
sleep. The levels start to climb a few hours before waking. The overall shape of the corticotropic profile is not
During shifted sleep, the cortisol rhythm remains tied to markedly affected by the absence of sleep or by sleep at
clock time. There is a weak sleep-related component. The an unusual time of day.
presence of sleep causes inhibition and maintains low levels During sleep deprivation, the nocturnal cortisol is higher
early in the sleep period (Fig. 305). Awakening at the end (amplitude of oscillation reducedi.e., early night not as
low, early AM not as high).
of sleep is associated with a burst of cortisol secretion.

Sleep Deprivation and Sleep Loss

deprivation induces less recovery (less impact on morning
Sleep deprivation induces a 15% decrease in amplitude of stimulation by ACTH). Older adults tend to have higher
the 24-hour cortisol rhythm (i.e., peak to trough of excursion evening cortisol levels (Fig. 306; see also Box 302).
is smaller). In the absence of sleep, the nadir in the early part
of the sleep period is not as low and the peak following in
SLEEP AND THE THYROID AXIS
the morning is not as high (absence of stimulating effects of
awakening). However, sleep fragmentation causes a burst of TSH (secreted by the pituitary) stimulates the thyroid gland
cortisol and higher morning levels. The night of sleep to secrete the hormones thyroxine (T4) and triiodothyronine
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618 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders

20

Plasma cortisol (g/dL)

15

22 02
10

0 22 02
18 22 02 06 1 18 22 02 06 10 14 18 22
When sleep is absent
Nocturnal sleep rise in cortisol starts
Nocturnal sleep deprivation earlier - sleep inhibitory
Daytime sleep

FIGURE 305 When sleep is present, it is inhibitory on cortisol secretion. When sleep is absent, the start of the rise in cortisol is earlier. The vertical bar shows the
time of onset in the upswing in cortisol secretion. An enlargement of the areas is shown to the right. Adapted from Van Cauter E, Spiegel K: Circadian and sleep
control of hormones. In Turek FW, Zee PC (eds): Regulation of Sleep and Circadian Rhythms. New York: Marcel Dekker, 1999, p. 399.

Mean evening
25 cortisol level (g/dL)
7
Plasma cortisol (g/dL)

20 6
ns
15 5
4
10 3
2
5
1
0 0
18 22 02 06 10 14 18 22 02 Day 1 Day 2
Clock time

25
7
Plasma cortisol (g/dL)

20 P  0.003
6

15 5
4
10 3
2
5
1
0 0
18 22 02 06 10 14 18 22 02 Day 1 Day 2
Clock time
FIGURE 306 During sleep deprivation, the nocturnal cortisol is greater. Mean profiles of plasma cortisol for two groups of
healthy young subjects during a 32-hour period with normal sleep (upper panel) and sleep deprivation (lower panel). The
dark bar represents the sleep period. The shaded areas represent cortisol secretion between 18:00 and 23:00 on Day 1 and Day
2 (before and after the night shown). The mean of these areas determines the mean evening cortisol level (bar graphs). In the
top panel, the mean of the two shaded areas is virtually identical (bar graph to the right of the upper panel). In the
bottom panel, sleep deprivation results in an increase in the mean evening cortisol level (bar graph to the right of
the bottom panel). Thus, sleep deprivation results in a higher nocturnal cortisol and higher late evening cortisol levels. From
Van Cauter E: Endocrine physiology. In Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine. Philadelphia:
Elsevier, 2005, p. 270.

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 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders 619

Plasma TSH (U/mL)

3

1
18 22 02 06 10 14 18 22 02 06 10 14 18 22

Nocturnal sleep
Nocturnal sleep deprivation
Daytime sleep

FIGURE 307 Mean 24-hour profiles of levels of plasma thyroid-stimulating hormone (TSH) during a 53-hour
period including 8 hours of nocturnal sleep (dark blue bar), 28 hours of continuous wake (white bar), and 8
hours of daytime sleep (light blue bar). Subjects were young healthy men. The shaded area corresponds to
normal 24-hour conditions. The vertical bar at each time point represents the SEM. The nocturnal elevation of
plasma TSH remains synchronized to clock time even when sleep is shifted. The effect of nocturnal sleep is an
inhibition of TSH secretion that is relieved by sleep deprivation, resulting in an augmentation of the nocturnal
TSH rise. The inhibitory effects of sleep on TSH secretion depend on the time of day. Daytime sleep does not
significantly alter (inhibit) TSH levels, which are already low at that time of day because of circadian
influences. Adapted from Van Cauter E, Spiegel K: Circadian and sleep control of hormones. In Turek FW, Zee PC
(eds): Regulation of Sleep and Circadian Rhythms. New York: Marcel Dekker, 1999, p. 399, with permission.

(T3). TSH production is controlled by thyrotropin-releasing BOX 303

hormone (TRH), which is manufactured in the hypothala-
mus and transported to the anterior pituitary gland where it
stimulates TSH production and release. Somatostatin is also
produced by the hypothalamus and has an opposite effect on
the pituitary production of TSH, decreasing or inhibiting its
release.
The level of thyroid hormones (T3 and T4) in the blood
has an effect on the pituitary release of TSH. When the levels
of T3 and T4 are low, the production of TSH is increased, and
conversely, when levels of T3 and T4 are high, TSH produc-
tion is decreased. This effect creates a regulatory negative
feedback loop.
TSH Secretion
Daytime levels of plasma TSH are low and relatively stable.
There is a rapid elevation of TSH starting in the early evening
and culminating in a nocturnal maximum occurring around
the end of the first third of the sleep period (Box 303 and
Fig. 307). The latter part of the sleep period is associated
with a progressive decline in TSH. Because the start of the
nocturnal rise in TSH occurs well before sleep onset, it
likely reflects a circadian effect. Sleep exerts an inhibitory
influence on TSH secretion,1,2 and sleep deprivation relieves
this inhibition, resulting in higher TSH during the night. The
inhibition of TSH by sleep is greatest during stage N3 sleep
and the inhibition is greater on recovery sleep from prior
sleep deprivation (more stage N3, higher delta power).
The suppression of TSH by sleep depends on the time of
day. When sleep occurs during daytime hours, TSH secre-
tion is not suppressed significantly below normal daytime
levels. Thus, the inhibitory effect of sleep on TSH secretion
Thyroid-Stimulating Hormone (TSH) and
the Thyroid Axis
Circadian control (higher at night).
Peak in midsleep period (middle of the night).
Stable level during the day.
Sleep inhibitory at night (higher if no sleep).
appears to be operative when the nighttime elevation has
taken place, indicating an interaction of the effects of circa-
dian time and the effects of sleep. Awakenings interrupting
nocturnal sleep appear to relieve the inhibition of TSH
and are consistently associated with a short-term TSH
elevation.
Thyroid Hormone Levels
Circadian and sleep-related variations in thyroid hormones
have been difficult to demonstrate. Thyroid hormones are
bound to serum proteins, and thus, peripheral concentra-
tions are affected by diurnal variations in hemodilution
caused by postural changes. However, under conditions of
sleep deprivation, the increased amplitude of the TSH
rhythm may result in a detectable increase in plasma T3
levels, paralleling the nocturnal TSH rise.
SLEEP AND PROLACTIN SECRETION
Pituitary prolactin (PRL) secretion is regulated by neuroen-
docrine neurons in the hypothalamus, the most important
ones being the neurosecretory tuberoinfundibulum (TIDA)
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620 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders

FIGURE 308 Mean 24-hour profile of plasma prolactin 250

(PRL) during a 53-hour period including 8 hours of nocturnal
sleep (dark blue bar), 28 hours of continuous wakefulness

Plasma prolactin
200

(% of mean)
(nocturnal hours: white bar), and 8 hours of daytime sleep
(light blue bar). Subjects were young healthy men. The
150
shaded area corresponds to normal 24-hour conditions.
The vertical bar at each time point represents the SEM. The
temporal pattern of PRL secretion is mainly regulated by 100
sleep so that shifted sleep is associated with a shift in the
secretion of PRL. Adapted from Van Cauter E, Spiegel K: 50
18 22 02 06 10 14 18 22 02 06 10 14 18 22
Circadian and sleep control of hormones. In Van Cauter E,
Spiegel K (eds): Circadian and Sleep Control of Hormones. In Nocturnal sleep
Turek FW, Zee PC (eds): Regulation of Sleep and Circadian Nocturnal sleep deprivation
Rhythms. New York: Marcel Dekker, 1999, p. 399. Daytime sleep

BOX 304 TABLE 301

Sleep and Prolactin Summary of Major Control of Major Hormones

PRLtiming of secretion is primarily sleep related (sleep HORMONE PRIMARY SECONDARY

stimulatory). GH Sleep (stimulatory, Weak circadian effect
PRL secretion has a possible role in circadian control of onset stage N3) (increased GH
REM sleep and in the amount of stage N3 sleep. secretion at night)
PRL = prolactin; REM = rapid eye movement. low somatostatin?
ACTH, cortisol Circadian (peaks Sleep inhibitory
around 7 AM)
neurons of the arcuate nucleus, which secrete dopamine to TSH Circadian (peaks Sleep inhibitory
act on the dopamine-2 receptors of lactotrophs, causing around 2 AM)
inhibition of PRL secretion. Thyrotropin-releasing factor
(TRH) has a stimulatory effect on PRL release. Vasoactive Prolactin Sleep (stimulatory) Circadian effect
sleep is more
intestinal peptide (VIP) secretion by the hypothalamus also
stimulatory when it
stimulates PRL release.
occurs at night
PRL levels show a bimodal pattern. They are minimal
ACTH = adrenocorticotropic hormone; GH = growth hormone; TSHthyroid-
around noon, increase somewhat during the afternoon, stimulating hormone.
and then increase shortly before sleep onset (Fig. 308).
Decreased dopaminergic inhibition of PRL during sleep
is likely to be the primary mechanism underlying noctur- prolactin secretion may be stimulation of REM sleep.
nal PRL elevation. In adults of both sexes, the nocturnal However, this has been demonstrated only in rodents. The
maximum corresponds to an average increase of more than effect may be observed 1 to 2 hours after treatment. The
200% above the minimum level. Morning awakenings and stimulatory effect of PRL on REM sleep depends on time of
awakenings interrupting sleep are consistently associated day (observed only during lightthe inactive period in
with a rapid inhibition of PRL secretion. Studies of the PRL rodents).
profiles during daytime naps or after shifts of the sleep period There is also some evidence for an involvement of PRL in
have consistently demonstrated that sleep onset, irrespec- stage N3 regulation. Stage N3 sleep is enhanced in patients
tive of the time of day, has a stimulatory effect on PRL with hyperprolactinemia and in women who breast-feed and
release1,2 (Box 304). Note that the stimulatory effect of sleep have high PRL levels compared with women who bottle-feed
on PRL secretion is greatest at night. their infants.6,7

Evidence for the Role of PRL in Summary of Control of Hormone Secretion

Regulation of Sleep
Several studies have examined the possible relationship
between pulsatile PRL release during sleep and the alterna-
tion of REM and nonrapid eye movement (NREM) stages.
Using power spectral analysis of the EEG, a close temporal
association between increased PRL secretion and delta wave
activity is apparent. Awakenings inhibit nocturnal PRL
release. Thus, fragmented sleep generally is associated
with lower nocturnal PRL levels. The primary effect of
A summary of the control of secretion of GH, cortisol, TSH,
and PRL is listed in Table 301. The table highlights that the
secretion of some hormones is tied to sleep and others to
circadian control. There may be a weaker secondary effect of
sleep on hormone secretion primarily under circadian
control and a weaker circadian effect on hormone secretion
primarily under sleep control. A mnemonic for remember-
ing the major control mechanisms: GPS ATC = Growth
hormone and Prolactin under Sleep-wake control and
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 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders
700
Total testosterone (ng/dL) 600
500
400
300
200
4 5 6 7 8 LEPTIN
Total sleep time (hours)
FIGURE 309 Morning levels of plasma total testosterone in healthy older men in
relation to the amount of their nocturnal total sleep measured by polysomnography. A
superimposed best-fit line illustrates the unadjusted bivariate correlation of these
variables. Total sleep time is highly correlated with the total testosterone the following
morning. From Penev PD: Association between sleep and morning testosterone levels in
older men. Sleep 2007;30:428, with permission.
ACTH (cortisol) and TSH primarily under Circadian
control.
SLEEP AND THE GONADAL AXIS
The 24-hour patterns of gonadotropin release and gonadal
steroid levels vary according to the stage of life and are
gender dependent.8,9 In prepubertal children, luteinizing
hormone (LH) and follicle-stimulating hormone (FSH) are
secreted in pulses of low amplitude, and a sleep onset
augmentation effect is present in the majority of both girls
and boys. As the child approaches puberty, the amplitude
of the nocturnal pulses increases and the diurnal rhythm
becomes more evident. A large nocturnal increase in gona-
dotropins is one of the hallmarks of puberty. In pubertal
boys, the nocturnal rise of testosterone parallels the elevation
of gonadotropins, whereas in pubertal girls, higher concen-
trations of estradiol occur during the daytime instead of the
nighttime.9 It has been proposed that the lack of parallelism
between the diurnal variation of gonadotropins and estradiol
reflects a 6- to 10-hour delay between gonadotropin stimula-
tion and the ovarian response related to the time required
for aromatization of estradiol.
In young adult men, the day-night variation of plasma LH
levels is dampened or even undetectable,10 whereas a marked
diurnal rhythm in circulating testosterone levels persists
with minimal levels in the late evening, and a clear nocturnal
elevation results in maximal levels in the early morning.11
Sleep fragmentation in normal men decreases the nocturnal
rise in testosterone if REM sleep does not occur. The sleep
related rise in testosterone appears to be linked to the first
REM period.11,12
In elderly men, the morning level of testosterone depends
on the amount of sleep. Higher levels correlate with more
sleep. A recent study has indicated that the amount of night-
time sleep is a strong predictor of morning testosterone
levels in healthy older men13 (Fig. 309).
In adult women, diurnal and pulsatile LH variations
are markedly modulated by the menstrual cycle. In
621
BOX 305
Sleep Loss, Leptin, Ghrelin
SLEEP LOSS IS ASSOCIATED WITH:
Impaired glucose metabolism.
Lower leptin levels.
Higher ghrelin levels.
Increased risk of obesity (chronic short sleep duration).
Secreted by adipose tissue.
Promotes satiety.
Leptin levels rise at night.
GHRELIN (PEPTIDE)
Secreted by the stomach.
Increases appetite.
Intake of food suppresses ghrelin secretion.
Levels increase in the first part of the night then fall in
the second part.
postmenopausal women, gonadotropin levels are elevated,
and show no consistent circadian patten.
LEPTIN AND GHRELIN
Appetite is regulated by the interaction between metabolic
and hormonal signals and neural mechanisms.14 The arcuate
nucleus of the hypothalamus has two opposing sets of neu-
ronal circuitry, appetite-simulating and appetite-inhibiting,
and several peripheral hormonal signals have been identified
that affect these neuronal regions.15 The peripheral signals
included leptin and ghrelin (Box 305). Leptin is primarily
secreted by adipose tissue and appears to promote satiety.15
Ghrelin is a peptide released primarily from the stomach.16
Studies in humans also indicate that ghrelin increases appe-
tite and food intake. Plasma ghrelin levels are rapidly sup-
pressed by food intake and then rebound after 1.5 to 2 hours,
paralleling the resurgence in hunger. Thus, leptin and ghrelin
exert opposing effects on appetite. Animal studies suggest
that leptin and ghrelin also have opposing effects on energy
expenditure (leptin increasing energy expenditure), but the
picture is less clear in humans. Under normal conditions, the
24-hour profile of human plasma leptin levels shows a
marked nocturnal rise. When leptin levels were studied with
continuous enteral nutrition, leptin levels still rose at night.17
Ghrelin levels typically rise during the first half of the night,
then decrease in the second half even in the fasting condi-
tion.18 A mnemonic for the effect of Ghrelin is Gotta Have
Food.
There have been several studies of the effect of sleep loss
on ghrelin and leptin levels. The results have varied between
studies. However, in general, sleep loss leads to increased
ghrelin and decreased leptin.14 This would tend to increase
food intake and perhaps decrease energy utilization. Some
of the variable findings from studies may been due to the fact
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622 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders
that nocturnal sleep times were not very reduced or that
variable degrees of obesity were present in the populations
studied.
OBESITY AND SLEEP DURATION
Numerous cross-sectional population studies have tried to
determine whether obesity is associated with sleep loss.14
Two longitudinal studies are mentioned. Analysis of data
from the first National Health and Nutrition Examination
Survey (NHANES I) indicated that subjects between the ages
of 32 and 49 years with self-reported sleep durations at base-
line of less than 7 hours had higher average body mass
indices (BMIs) and were more likely to be obese than sub-
jects with sleep durations of 7 hours.19 A second longitudinal
study analyzed the association between sleep and BMI over
a 13-year period and reported that the odds ratio for sleep
duration predicting obesity was 0.50, which means that
every extra hour increase of sleep duration was associated
with a 50% reduction in risk of obesity.20 In humans, part of
the tendency for weight gain after sleep loss is that sleep loss
may reduce energy expenditure. In rodents, leptin increases
energy expenditure and ghrelin decreases expenditure. In
rodents, sleep loss experiments involve constant movement
or other activity and rodents do not gain weight even
with increased food intake. The importance of leptin and
ghrelin on energy expenditure in humans remains to be
documented.
SLEEP AND GLUCOSE TOLERANCE
Sleep has important effects on glucose metabolism, suggest-
ing that sleep disturbances may adversely affect glucose tol-
erance. In a study by Scheen and coworkers,21 subjects
received a constant glucose infusion during (1) nocturnal
sleep, (2) nocturnal sleep deprivation, and (3) daytime
recovery sleep. The investigators analyzed plasma glucose
levels, insulin secretion rates (ISRs), and plasma GH and
cortisol levels. Plasma glucose and ISR markedly increased
during early nocturnal sleep and returned to presleep levels
during late sleep. These changes in glucose and ISR appeared
to reflect the predominance of slow wave activity (stage N3)
in early sleep and of REM and wake stages in late sleep.
Major differences in glucose and ISR profiles were observed
during sleep deprivation as glucose and ISR remained essen-
tially stable during the first part of the night and then
decreased significantly, despite the persistence of bedrest and
constant glucose infusion.
During daytime recovery sleep, slow wave activity (stage
N3) was increased, glucose levels peaked earlier during noc-
turnal sleep, and the decreases of glucose and ISR in late
sleep were reduced by one half. Thus, sleep has important
effects on brain and tissue glucose utilization, suggesting that
sleep disturbances may adversely affect glucose tolerance.
Spiegel and colleagues22 studied 11 healthy volunteers using
a protocol of experimental sleep restriction (4 hr/night 6
nights) followed by a recovery period (12 hr/night 6
nights). The study found decreased glucose tolerance in the
sleep-debt condition compared with the fully rested condi-
tion. Evening cortisol concentrations were raised and activ-
ity of the sympathetic nervous system was increased in the
sleep-debt condition.
Gottlieb and associates23 analyzed a subsample of the
population from the Sleep Heart Health Study (1486 sub-
jects; 722 men and 764 women).
The usual sleep time was obtained by self-report. Statisti-
cal adjustments made for numerous covariates including age,
gender, race, apnea-hypopnea index (AHI), and waist girth.
Lower sleep time was associated with impaired glucose toler-
ance and diabetes mellitus based on serum glucose measure-
ments (fasting and 2-hr).
Chapter 17 discusses the evidence that OSA is associated
with impaired glucose tolerance and an increased risk of
developing diabetes. The major confounder is the presence
of obesity. A cross-sectional analysis of the Sleep Heart
Health data24 was performed (2588 participants aged 52
96 yr; 46% men) on individuals without known diabetes.
Sleep-disordered breathing (SDB) was defined as a respira-
tory disturbance index of 10 events/hr or greater. Impaired
fasting glucose (IFG), impaired glucose tolerance (IGT),
occult diabetes, and body weight were classified according
to recent accepted guidelines. Participants with and without
SDB were compared on prevalence and odds ratios for mea-
sures of impaired glucose metabolism (IGM) after adjust-
ing for age, sex, race, BMI, and waist circumference. SDB was
observed in 209 non-overweight and 1036 overweight/obese
participants. SDB groups had significantly higher adjusted
prevalence and adjusted odds ratios of IFG, IFG plus IGT,
and occult diabetes. The adjusted odds ratio for all subjects
was 1.3 for IFG, 1.2 for IGT, 1.4 for IFG plus IGT, and 1.7
for occult diabetes. SDB was associated with occult diabetes,
IFG, and IFG plus IGT after adjusting for age, sex, race, BMI,
and waist circumference. The magnitude of these associa-
tions was similar in non-overweight and overweight partici-
pants. The consistency of associations across all measures of
IGM and body habitus groups and the significant association
between SDB and IFG plus IGT (a risk factor for rapid pro-
gression to diabetes, cardiovascular disease, and mortality)
suggest the importance of SDB as a risk factor for clinically
important levels of metabolic dysfunction. Chapter 17 dis-
cusses some studies showing that continuous positive airway
pressure (CPAP) may improve glucose control in some
patients with both obstructive sleep apnea (OSA) and dia-
betes. At least in some studies, CPAP treatment has more
significant effects in patients who are not obese.
SLEEP AND GASTROINTESTINAL PHYSIOLOGY
AND DISORDERS
Gastric and Intestinal Function
There is a peak in acid secretion occurring between 10 PM
and 2 AM. Basal waking acid secretion is minimal unless
stimulated by food. The peak in acid secretion is under
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 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders
BOX 306
Important Facts about Gastroesophageal Reflux
GER AND SLEEP
4550% of patients with GER have nocturnal symptoms
Prolonged sleep latency.
Frequent awakenings.
Fewer but longer GER episodes at night.
GER is common in OSA patients (5075%).
GER AND PULMONARY COMPLICATIONS
Exacerbation of nocturnal asthma.
Nocturnal pulmonary aspiration.
Increased incidence of GERD in pulmonary fibrosis.
Sleep-related laryngospasm (possible role for GER).
GER AND GASTROINTESTINAL COMPLICATIONS
Erosive esophagitis.
Increased risk for Barretts esophagus?
Increased risk esophageal carcinoma?
Nocturnal GER.
May increase risk of GER complications.
Can cause significant sleep disturbance.
NOCTURNAL MECHANISMS WORSENING DAMAGE
FROM GER
Saliva production virtually stops during sleep.
Swallowing occurs only after arousal from sleep.
Prolonged ACT.
Transient LES relaxation after arousal from sleep or during
wake.
Most sleep-related reflux occurs during or following
arousal from stage N2 sleep.
ACT = acid contact time; GER = gastroesophageal reflux; GERD =
gastroesophageal reflux disease; LES = lower esophageal sphincter;
NREM = nonrapid eye movement; OSA = obstructive sleep apnea.
circadian control and is not definitely altered by sleep or
sleep stage.25 There is delayed gastric emptying during sleep.
Intestinal and colonic activity are generally decreased during
sleep. Rectal motor activity increases during sleep but pro-
pulsion is retrograde. This and the fact that anal sphincter
tone (while reduced) remains higher than rectal tone prevent
anal leakage during sleep.
Gastroesophageal Reflux and Sleep
Normal Gastroesophageal Physiology
The lower esophageal sphincter (LES) prevents reflux of
stomach contents into the esophagus. In the upright posi-
tion, postprandial gastric distention causes brief relaxation
of the LES with transient reflux that is quickly cleared. A
number of factors assist in clearance or neutralization of
stomach contents: (1) volume clearancetwo or three swal-
lows induce clearance of reflux material, and (2) acid
neutralizationsaliva itself buffers the acidity of refluxed
material. These mechanisms quickly return the distal
623
BOX 307
pH Monitoring Definitions
pH PROBE POSITION
pH probe placed 5 cm H2O above LES (GE junction about
42 cm H2O from nares).
LES pressure determined manometrically (pressure
transducers).
LES position determined by pH measurement.
Probe is inserted until pH drops to 1.52.5, is slowly
withdrawn until pH = 4, and then slowly withdrawn to
57 cm H2O above this point.
DEFINITIONS
Reflux episodespH drops below 4.
Clearance defined as when PH returns to 4.
Clearance intervaltime from initial pH drop below 4
until return to above 4.
Acid contact timetime below pH of 4.
Expresses as % of time in 24 hours.
Normally 46%.
GE = gastroesophageal; LES = lower esophageal sphincter.
esophagus to pH 5.5 to 6.5 (normal esophageal pH) (Boxes
306 and 307).
Nocturnal Gastroesophageal Reflux
Gastroesophageal reflux (GER) during sleep is common,
with up to 10% of the population reporting symptoms
of nocturnal reflux in survey studies.26,27 In a Gallup poll of
heartburn patients, 79% reported nighttime heartburn, of
which 75% noted that heartburn negatively affected their
sleep. Despite medical therapy for GER, only 49% had ade-
quate control of their nocturnal symptoms.27,28 Nocturnal
GER is potentially more injurious than diurnal GER because
acid clearance mechanisms are impaired during sleep.
When episodes of GER occur during sleep, acid contact time
(ACT) is prolonged. During sleep salivary flow virtually
stops and the frequency of swallowing is very decreased (e.g.,
6/hr). The clearance of refluxed material occurs only after
arousal from sleep. Most nocturnal GER episodes occur
during prolonged wake or after arousal from stage N2 sleep.
Freidin and coworkers28 compared normal subjects and
patients with reflux esophagitis with nocturnal monitoring
of pH, esophageal manometry, and sleep stage. The LES pres-
sures were similar in normal subjects and patients. Both
groups had similar LES pressure during both wakefulness
and sleep. The patients had many more reflux episodes.
However, most nocturnal reflux episodes occurred during
wake periods and some occurred after brief arousals from
sleep. Transient lower esophageal sphincter relaxations
(TLESRs) accounted for most of these episodes. Symptom-
atic reflux (especially at night) is believed to be a possible
risk factor for the development of esophageal adenocarci-
noma29 and Barretts esophagus30 (a precursor of adenocar-
cinoma). However, not all studies have found a higher
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624 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders
L-EOG
R-EOG
C4-A1
O2-A1
Chin EMG
Flow
Chest
Abdomen
pH distal
8
6
4
2
0
FIGURE 3010 An episode of gastroesophageal reflux (GER) follows an arousal. Note that the pH drops below 4.
EMG = electromyogram; EOG = electro-oculogram. From Berry RB, Harding SM: Sleep and medical disorders. Med Clin North
Am 2004;88:679703.
incidence of complaints of nocturnal reflux in patients with
Barretts esophagus.31 Symptoms of nocturnal GER include
multiple awakenings, substernal burning or chest discom-
fort, indigestion, and heartburn. Other symptoms include a
sour or bitter taste in the mouth, regurgitation, coughing,
and choking.
pH Monitoring
Esophageal pH testing (see Box 307) is used to diagnose
GER and has a sensitivity and specificity of approximately
90%.32 It can be performed as an ambulatory study or inte-
grated with polysomnography (sleep monitoring) for temp-
oral correlation of sleep-related events such as arousals.
Esophageal pH testing is performed by placing a pH probe in
the distal esophagus (5 cm above the LES). Many laboratories
utilize dual pH probes, in which a proximal pH probe is also
placed at the upper esophageal sphincter or in the pharynx.
A GER episode is defined by the presence of material that has
a pH less than 4. Figure 3010 shows a GER event after an
arousal from sleep. ACT, defined as the time with a pH less
than 4, is often computed as absolute time or as a percentage
of monitoring time or sleep time. A normal ACT is often
assumed to be less than 4%. GER episodes should be sus-
pected on routine polysomnography if there is an arousal
followed by a prolonged period of increased chin electro-
myogram (manifestation of swallowing) (see Fig. 3010).
Nocturnal Asthma and GER
Recently, there has been considerable interest in the rela-
tionship between nocturnal GER and asthma. Some
Arousal
experimental evidence suggests that GER can worsen airway
function with or without aspiration into the lungs. Jack
and colleagues33 monitored both tracheal and esophageal
pH in four nocturnal asthmatics with GER. There were
37 episodes of esophageal reflux of which 5 episodes were
associated with a fall in tracheal pH. Tracheal acid episodes
were associated with prolonged reflux episodes, nocturnal
awakenings, and bronchospasm during the night. Aspira-
tion, however, may not be required to trigger changes in
bronchial tone. Afferent vagal fibers are present in the lower
esophagus and could trigger changes in bronchial tone
when stimulated by gastric contents. Cuttitta and associ-
ates34 evaluated spontaneous reflux episodes and airway
patency during the night in seven asthmatics with GER.
Multiple stepwise linear regression analysis revealed that
the most important predictor of change in lower respira-
tory resistance was the duration of esophageal acid expo-
sure. Both long and short GER episodes (those < 5 min
and those > 5 min) were associated with higher respiratory
resistance compared with baseline. These data collectively
suggest that esophageal acid is able to elicit nocturnal
bronchoconstriction. Given these findings, an important
question is whether or not treatment of nocturnal GER
can improve asthma. Some uncontrolled studies have shown
a benefit in asthma with aggressive treatment of GER.35
A large parallel-group, randomized, double-blind study of
esomperazole for treatment of poorly controlled asthma
(patient did not complain of GER) found no difference
in episodes of asthma excerbations.36 GER was found in
40% of patients using pH monitoring (asymptomatic). No
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 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders
subgroup of patients could be identified in which treatment
of GER improved asthma. The investigators concluded that
GER (in patients asymptomatic with respect to GER) is
unlikely to be a major factor in uncontrolled asthma.
However, this group of patients did not have GER symp-
toms. Treatment of patients with asthma and symptomatic
GER could be considered (for GER alone) but may also
help asthma in individual patients.
GER and OSA
Given the negative intrathoracic pressure during obstructive
apnea and the frequent arousals from sleep, one would
suspect that nocturnal GER is common in patients with
OSA. Green and coworkers37 prospectively examined 331
OSA patients. Significant nighttime GER was found in 62%
of subjects before OSA treatment. Patients compliant with
CPAP had a 48% improvement in their nocturnal GER
symptoms. There was no change in nighttime reflux symp-
toms if patients did not use CPAP. Furthermore, there was
a strong correlation between higher levels of CPAP and
improvement in nocturnal GER symptom scores (higher
pressure levels associated with more improvement). This
study shows that nocturnal reflux is common in OSA patients
and that nasal CPAP decreases the frequency of nocturnal
GER symptoms. Of note, the fact that nocturnal GER is
common in OSA patients and that CPAP reduces GER does
not necessarily prove that OSA causes GER. In some studies,
episodes of GER were not correlated with apneic events.38
CPAP by increasing the pressure gradient between the thorax
and the stomach may also reduce GER independent of the
effects of CPAP on OSA. Tawk and colleagues39 studied a
group of OSA patients (AHI > 20/hr) and a 24-hour ACT of
at least 6%. They performed 24-hour pH monitoring before
and after 1 week of CPAP. The final monitoring was per-
formed with the subjects wearing CPAP at night. The ACT
fell as did the number of reflux episodes (Fig. 3011). Eighty-
one percent of subjects had ACT reduced to normal range
(<4%).
Sleep-Related Laryngospasm
GER may also have a role in sleep-related laryngospasm
(SRL). Episodes of SRL consist of the patient abruptly awak-
ening with an intense feeling of suffocation often accompa-
nied with stridor and choking sensations.40 Other features
include intense anxiety, rapid heart rate, sensation of impend-
ing death, and residual hoarseness. The differential diagnosis
for SRL includes OSA, epilepsy, sleep choking syndrome,
sleep terrors, vocal cord dysfunction, and other upper airway
pathologies. Thurnheer and associates41 noted that 9 of 10
patients with SRL had GER documented by esophageal
pH testing. Six patients responded to antireflux therapy,
showing that GER may be associated with SRL.
Treatment of Nocturnal GER
Patients should not eat for at least 2 hours before bedtime
and avoid foods that promote GER, including high-fat foods,
caffeine, chocolate, mint, alcohol, tomato products, citrus,
625
150
p0.01
125
100 supine position
Reflux Events
75
48.4  36.8
50
25
8.6  11
0
Before CPAP After CPAP
FIGURE 3011 Continuous positive airway pressure (CPAP) reduced the reflux events
in the supine position in patients with obstructive sleep apnea (OSA) and GER. From
Tawk M, Goodrich S, Kinasewitz G, Orr W: The effect of 1 week of continuous positive airway
pressure treatment in obstructive sleep apnea patients with concomitant gastroesophageal
reflux. Chest 2006;130:10031008.
and sodas. Medications that promote reflux should be
avoided, including calcium channel blockers, theophylline,
prostaglandins, and bisphosphonates. Smoking significantly
decreases LES pressure, so all patients should be encouraged
to stop smoking. Patients should lose weight if they are obese
and sleep in loose-fitting clothing. Positional therapy can
also be used. Sleeping with the head of the bed elevated 6
inches with a full-length wedge or placing blocks under the
head of the bed may be useful. The right lateral decubitus
position worsens GER, whereas the left lateral decubitus
posture seems to be the best sleep position for sleep-
related GER.42
Medications to treat sleep-related GER include antacids
for acute symptom control, H2 receptor antagonists, proton
pump inhibitors, and prokinetic agents.43 H2 receptor antag-
onists provide heartburn relief in 60% of patients and can be
given before sleep onset. Proton pump inhibitors provide
superior gastric acid suppression. One study found that
40 mg of omeprazole with dinner, or omeprazole, 20 mg,
before breakfast and with dinner, resulted in better gastric
acid suppression than giving 40 mg before breakfast only.44
Of note, proton pump inhibitors should be given before
the evening meal rather than before bedtime to treat noc-
turnal GER. Some data suggest there may be nocturnal acid
breakthrough despite proton pump inhibitor therapy.45
Whether nocturnal gastric acid breakthrough is clinically
important in GER is not known. Metoclopramide is the only
prokinetic agent available in the United States and has a high
prevalence (2050%) of central nervous system side effects.
Prokinetic agents can be used concomitantly with gastric
acidsuppressive agents. Antireflux surgery, primarily fun-
doplication (both open and laparoscopic methods), is suc-
cessful in 80% to 90% of patients. Long-term results, however,
show that many surgically treated patients use antireflux
medications regularly.46
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626 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders
FIGURE 3012 Location of tender points used to diagnose fibromyalgia. From Wolfe
F, Smythe HA, Yunus MB, et al: The American College of Rheumatology 1990 criteria for the
classification of fibromyalgia: report of the multi-center criteria committee. Arthritis
Rheum 1990;33:160172.
SLEEP AND RHEUMATOLOGY
Fibromyalgia Syndrome
Manifestations of Fibromyalgia
Fibromyalgia syndrome (FS) is defined by the American
College of Rheumatology as the presence of widespread
musculoskeletal pain for at least 3 months, which is bilateral
above and below the waist, including axial pain and the pres-
ence of 11 of 18 tender points47 (Fig. 3012). FS should be
considered a syndrome rather than a disease process. Fibro-
myalgia affects about 3% of the population aged 30 to 50
years and 70% to 90% of patients are women.48 Depression
is common in the disorder. The pathophysiology of FS is very
complex.4952 A possible mechanism is thought to be central
sensitization of nociceptive neurons in the dorsal horn of the
spinal cord with activation of N-methyl-D-aspartate recep-
tors. This central sensitization results in generalized height-
ened pain sensitivity caused by pathologic nociceptive
processing within the central nervous system. There is a
threefold increase in substance P and a decrease in serotonin
levels in the cerebrospinal fluid.52
Sleep in FS
Sleep complaints are common and include nonrestorative
sleep, fragmented sleep, and insomnia. Poor sleep seems to
worsen pain symptoms in 67% of the patients.48 Sleep studies
in FS patients have shown decreased total sleep time,
TABLE 302
Treatments for Fibromyalgia
Cognitive behavioral treatment
Exercise
Anticonvulsants
Pregabalin* (Lyrica)
Gabapentin (Neurontin)
Muscle relaxants
Baclofen
Cyclobenzaprine
Antidepressants
TCAs
Amitriptyline (2550 mg qhs)
SSRIs (if associated depression)
SNRIs
Venlafaxine (Effexor)
Duloxetine* (Cymbalta)
Milnacipran* (Savella)
*FDA approved for treatment of fibromyalgia.
FDA = U.S. Food and Drug Administration; SNRI = selective norepinephrine
reuptake inhibitor; SSRIs = selective serotonin reuptake inhibitors; TCAs =
tricyclic antidepressants.
decreased stage N3 and REM sleep, and increased arousals.48
An interesting EEG pattern (alpha sleep or alpha-NREM
anomaly) was first described in FS patients by Roizenberg
and coworkers53 and Branco and colleagues.54 This is charac-
terized by prominent alpha activity (813 Hz) persisting into
NREM sleep (alpha intrusion). Alpha activity is normally
present during relaxed wake and after brief awakenings
(arousals) but is normally virtually absent during stages N2
and N3 except as associated with arousals. Alpha intrusion
into stage N3 (slow wave or delta sleep) is called alpha-delta
sleep. Since that time, it has been recognized that the alpha-
NREM sleep anomaly is not specific for FS and is not present
in all patients with FS. Other groups in which the alpha-
NREM sleep anomaly can be found include patients with
chronic pain syndromes, depression, and diverse causes of
nonrestorative sleep. Indeed, alpha sleep has been seen in
up to 15% of normal subjects.55 In a variant of alpha sleep
(phasic alpha activity), alpha intrusion is seen mainly during
stage N3 rather than being present diffusely in NREM sleep.
In one study, phasic alpha activity seemed to be present in FS
patients with prominent sleep disturbance, subjective feeling
of superficial sleep, and more pain and stiffness.53 Chapter 4
contains sleep tracings illustrating the alpha anomaly.
Treatment of FS
Treatments for FS include antidepressants, anticonvulsants
(to treat pain), hypnotics, muscle relaxers, cognitive therapy,
exercise, biofeedback, and hypnosis.56,57 Patients should
incorporate good sleep hygiene habits. Furthermore, screen-
ing for primary sleep disorders is also indicated. Of note, FS
patients have a higher prevalence of restless legs syndrome
than controls.58 Some FS patients have clinical improvement
with low doses of antidepressants, whereas others require the
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 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders 627

Sleep time Sleep deprivation

30

Aldosterone (ng/dL)
20

10

3
PRA (ng/mL/h)

18 22 2 6 10 14 18 18 22 2 6 10 14 18
Clock time Clock time

FIGURE 3013 Mean 24-hour profiles of plasma renin activity (PRA) and aldosterone in eight normal young men during
normal nocturnal sleep and acute sleep deprivation. The vertical bar at each time point represents the SEM. Sleep deprivation
blunts the nocturnal increase in PRA and aldosterone. From Charloux A, Gronfier C, Chapotot F, et al: Sleep deprivation blunts
the nighttime increase in aldosterone release in humans. J Sleep Res 2001;10:29, with permission.

usual doses needed for an antidepressant effect. Tradition-
ally, low doses of tricyclic antidepressants (both serotonin
and norepinephrine reuptake inhibitors) such as amitrypti-
line 25 to 50 mg qhs were used for FS.59 The selective sero-
tonin reuptake inhibitors (SSRIs) have not been very effective
as treatment for FS unless depression was present. Two med-
ications selectively blocking reuptake of both serotonin and
norepinephrine (SNRIs) are U.S. Food and Drug Adminis-
tration (FDA) approved for treatment of FS. These medica-
tions are duloxetine (Cymbalta) and milnacipran (Savella)57
(Table 302). Venlafaxine (Effexor, also an SNRI) has also
been used but is not FDA approved for FS. The SNRIs appear
to work in both depressed and nondepressed patients with
FS.6063 Pregabalin (Lyrica) is an anticonvulsant that has also
been FDA approved for FS. Gabapentin is another anticon-
vulsant that has been used for chronic pain syndromes
including FS (not FDA approved for FS). Both pregabalin
and gabapentin have been shown to have benefit in FS
patients.64,65 Muscle relaxants such as cyclobenzaprine have
also been used.66 Studies have shown benefit from treatment
of FS with sodium oxybate.67,68
Sodium oxybate is believed to work in FS by improving
sleep quality. Sodium oxybate is currently FDA approved for
treatment of narcolepsy (cataplexy and daytime sleepiness).
An application was made to the FDA for an indication for
the use of sodium oxybate as a treatment for FS. However,
this application was rejected in part because the large FS
population and the potential for abuse of medication (date
rape drug).
SLEEP AND RENAL
Renin-Aldosterone and Sleep
Water and sodium homeostasis depends on coordination of
a number of factors including several hormones. Arginine
vasopressin (AVP) is secreted by the posterior pituitary and
is also known as antidiuretic hormone (ADH). AVP is
secreted in bursts but is independent of sleep stage. AVP
results in reabsorption of water from the collecting duct of
the kidney. Renin is secreted by the juxtaglomerular cells of
the kidney and aldosterone secreted by the adrenal cortex.
Renin hydrolyzes angiotensinogen (produced by the liver) to
produce angiotensin I. Angiotensin I is metabolized by lung
endothelial cells containing angiotensin-converting enzyme
(ACE) to angiotensin II. Angiotensin II is a potent vasocon-
strictor and also stimulates the adrenal to produce aldoste-
rone. Aldosterone causes absorption of sodium and water
and excretion of potassium. Atrial natriuretic peptide (ANP)
is secreted by the atrial myocytes in response to stretch and
other influences. ANP causes an increase in the renal excre-
tion of sodium and is a mechanism to respond to fluid over-
load. ANP is elevated in untreated sleep apnea (negative
intrathoracic pressure swings stretch the atria), resulting in
nocturia. Patients with untreated OSA have nocturnal natri-
uresis. Urine volume and electrolyte secretion is normally
lower at night. In particular, REM sleep is associated with
decreased urine flow and increased osmolality.
Plasma renin activity (PRA) and aldosterone levels are
elevated during sleep.6972 This effect is mainly related to
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628 Chapter 30 Sleep and Nonrespiratory PhysiologyImpact on Selected Medical Disorders
sleep rather than circadian factors. The usual nocturnal
rise in PRA and aldosterone is blunted by sleep deprivation71
(Fig. 3013). PRA increases during NREM sleep and
decreases during REM sleep. REM sleep is associated with
increased sympathetic tone, which increases renin. This
seems inconsistent with lower renin during REM sleep.
However, the dip in renin during REM sleep may occur from
lower blood pressure and sympathetic tone during NREM
sleep. Renin activity is already sharply decreasing before
REM sleep occurs. At the transition from REM sleep to
NREM sleep, renin levels are already rising.
CLINICAL REVIEW QUESTIONS
1. Secretion of GH is most closely tied to which of the
following?
A. First period of stage N3.
B. First REM period.
C. Time of day (circadian).
D. Time of awakening.
2. Which of the following about PRL secretion is true?
A. It is predominantly under circadian control.
B. It is inhibited by sleep.
C. It is stimulated by sleep.
D. It is increased by dopaminergic signaling from the
hypothalamus.
E. It is inhibited by TRH.
3. Which of the following is true about cortisol secretion?
A. It is closely tied to timing of sleep.
B. Nocturnal levels are increased by sleep deprivation.
C. Lowest levels are in the morning.
D. Lowest levels are in the evening.
4. Which of the following is true about TSH secretion?
A. It is stimulated by sleep.
B. It is inhibited by sleep.
C. TSH stimulation is under circadian control.
D. A and B.
E. B and C.
5. Which of the following are NOT true about leptin and
ghrelin?
A. Ghrelin stimulates the appetite.
B. Leptin stimulates the appetite.
C. Eating reduces ghrelin secretion.
D. Ghrelin levels are higher at night.
E. Sleep loss decreases leptin and increases ghrelin.
6. A GER episode is defined by a pH less than which
number?
A. pH < 3.
B. pH < 4.
C. pH < 5.
D. pH < 6.
7. Which of the following states are true concerning noctur-
nal GER?
A. It typically occurs during sleep.
B. It occurs during wake or after arousals.
C. Acid clearance at night is normal.
D. Acid clearance at night is abnormal.
E. B and D.
Answers
1. A. GH secretion is linked to the first period of stage N3.
2. C. Sleep stimulates PRL secretion. Dopamine inhibits
PRL secretion and TRH increases it.
3. B. Cortisol secretion is under circadian control. Highest
cortisol levels are around 7 AM. The lowest levels are
during the first part of the sleep period. Sleep deprivation
increases nocturnal levels.
4. E. TSH secretion is under circadian control but is inhib-
ited by sleep.
5. B. Leptin induces satiety. The other statements are true.
6. B. pH < 4.
7. E. Nocturnal GER occurs after arousals. Acid clearance
is reduced because saliva secretion stops during sleep and
swallowing does not occur.
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35. Harding SM, Richter JE, Guzzo MR, et al: Asthma and gastro-
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37. Green BT, Broughton WA, OConnor JB: Marked improvement
in nocturnal gastroesophageal reflux in a large cohort of
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38. Graf KI, Karaus M, Heinemann S, et al: Gastroesophageal
reflux in patients with sleep apnea syndrome. Z Gastroenterol
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42. Khoury RM, Camacho-Lobato L, Katz PO, et al: Influence of
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Sleep and Neurologic Disorders
Chapter Points
AD is the most common cause of dementia and can be
associated with the irregular sleep-wake rhythm
disorder and sundowning. In early AD, there is a
decrease in stage N3. In late AD, there is a decrease in
REM sleep and an increase in the REM latency.
OSA is common in AD patients and, if successfully
treated with CPAP, can improve sleep quality and
mood as well as slow the rate of cognitive decline.
Donepezil (Aricept), a cholinesterase inhibitor, is used
in AD to improve cognition but is often associated
with insomnia. Morning dosing is suggested to
minimize sleep disturbance. Some studies have
suggested that evening doses of rivastigmine and
galantamine can improve sleep quality. Cholinesterase
inhibitors and cholinergic medications in general tend
to increase REM sleep. Rivastigmine has been reported
to cause RBD in AD patients.
PSP is characterized by vertical gaze palsy and
prominent sleep-maintenance insomnia (worse than in
AD) and nocturia. PSP patients have a large reduction
in the amount of REM sleep. PSG will often show
absence of vertical eye movements during REM sleep.
RBD occurs in approximately 13% to 30% of PSP
patients.
The sleep of patients with PD is impaired by rigidity,
tremor (tends to resolve with sleep onset), dyskinesias,
OSA, RBD, and nocturnal hallucinations. Patients with
PD can manifest excessive daytime sleepiness even if
OSA is not present. Modafinil may be helpful, although
the published evidence is conflicting.
PD+ disorders are manifested by parkinsonism
(bradykinesia and rigidity), no or decreased response
to levodopa, sensitivity to dopamine blockers, and a
more rapid course than PD. PD+ disorders include PSP,
DLBD, and MSA.
Patients with DLBD have prominent dementia much
earlier in the disease course compared with PD. The
patients frequently have visual hallucinations and are
exquisitely sensitive to dopamine blockers (can
Chapter 31
develop severe rigidity). The RBD is common in
patients with DLBD.
MSA patients have various amounts of striatonigral
degeneration (rigidity and bradykinesia),
olivopontocerebellar degeneration (cerebellar
dysfunction, ataxia, falls), and autonomic dysfunction
(erectile dysfunction, orthostatic hypotension, bladder
dysfunction). The RBD is very common in MSA
patients.
Stridor (especially during sleep) is a well-known
manifestation of MSA and denotes a poor prognosis.
FFI is a familial autosomal dominant prion disease with
progressive insomnia and dementia. PET shows a
characteristic absent or very low activity of the
thalamus.
There is a high prevalence of sleep apnea in patients
who have had a recent stroke. OSA is the most
common form of sleep apnea but central sleep apnea
(including CSB) can occur. If OSA is present, this is
associated with a worse prognosis but CPAP treatment
can improve outcomes.
SLEEP AND NEURODEGENERATIVE DISORDERS
Sleep complaints are very common in patients with neuro-
degenerative disorders (Box 311). Some basic knowledge
about these disorders is essential for the sleep clinician. The
major neurodegenerative disorders are discussed briefly with
an emphasis on the effects on sleep.
Synucleopathies
The synucleopathies are chronic and progressive disorders
associated with a decline in cognitive, behavioral, and auto-
nomic functions.1,2 The two major categories are taupathies
and alpha synucleopathies (Table 311). The taupathies are
disorders associated with intracellular disposition of abnor-
mally phosphorylated tau (a microtubule-associated protein)
usually expressed as neurofibrillary tangles, neurophil
threads, and abnormal tau filaments (Pick bodies). Tau
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632 Chapter 31 Sleep and Neurologic Disorders
BOX 311
Sleep Disorders in Neurodegenerative Disorders
Insomniasleep onset, sleep maintenance, fragmented
sleep
Hypersomnia
Sleep apnea syndromes
Hypersomnia due to the neurologic disorder
Excessive nocturnal motor activity (including RBD)
Circadian rhythm disorders
Sundowning
RBD = rapid eye movement sleep behavior disorder.
TABLE 311
Neurodegenerative Disorders
TAUPATHIES ALPHA SYNUCLEOPATHIES
Alzheimers disease (AD) Parkinsons disease (PD)
Progressive supranuclear Diffuse Lewy body dementia
palsy (PSP) (DLBD)
Corticobasal degeneration Multiple system atrophy
(CBD) (MSA)
Frontotemporal dementia
(FTD)
Picks disease
proteins are involved in maintaining the cell shape and serve
as tracks for axonal transport. The taupathy disorders include
Alzheimers disease (AD), progressive supranuclear palsy
(PSP), corticobasal degeneration (CBD), frontotemporal
dementia (FTD), and Picks disease. Alpha synuclein is a
protein that helps in the transportation of dopamine-laden
vesicles from the cell body to the synapses. The alpha synu-
cleopathies include Parkinsons disease (PD), diffuse Lewy
body dementia (DLBD), and multiple system atrophy (MSA).
Dementias
Dementia is defined as a clinical syndrome characterized by
acquired loss of cognitive and emotional abilities severe
enough to interfere with daily functioning.1,2 In evaluating
any patients with dementia, it is important to rule out treat-
able causes including medication side effects, hypothyroid-
ism, vitamin B12 deficiency, depression, and occult obstructive
sleep apnea (OSA). Pseudodementia of the elderly is due to
depression and can be associated with a short rapid eye
movement (REM) latency and high REM density. In con-
trast, patients with AD tend to have a low REM density, long
REM latency, and a reduction in the amount of REM sleep.
AD is by far the most common cause of dementia with
DLBD the next most common (Box 312).
Alzheimers Disease
AD is the most common cause of dementia (>60% of demen-
tias). The diagnosis is one of exclusion. The hallmark is a
BOX 312
Major Dementias
Alzheimers disease (6080%)
Diffuse Lewy body dementia (20%)
Others (vascular, metabolic)
gradual onset of short-term memory problems. The APO4E
genotype is a risk factor for AD. Sleep disturbance worsens
in parallel with cognitive dysfunction. Patients with AD
suffer from sundowning (Box 313), which is defined as noc-
turnal exacerbation of disruptive behavior or agitation in
older patients. This is likely the most common cause of insti-
tutionalization in patients with AD. Some of the key points
concerning AD are listed in Box 314.
Etiology of Sleep Disturbances in AD A number of factors may
contribute to sleep disturbance in AD. Degeneration of
neurons in a number of areas including the optic nerve,
retinal ganglion cells, and suprachiasmatic nucleus may con-
tribute to circadian rhythm disturbances in AD.35 These
patients may manifest the irregular sleep-wake rhythm dis-
order. Institutional factors can worsen circadian rhythm dis-
orders by decreasing normal zeitgebers (light and activity)
and disturbing nocturnal sleep (noise). Poor sleep hygiene
including daytime sleeping and decreased physical activity
may also impair sleep-wake rhythms.
Sleep Disturbances in AD A number of sleep disturbances are
present in AD and vary with the course of the illness (Table
312). Early in the illness, there is disruption of sleep-wake
rhythms, nocturnal awakenings, and decreased stage N3
sleep. Late in the disease course, there is a reduction in REM
sleep and increased REM latency as well as excessive daytime
sleepiness. Whereas both OSA and medications can contrib-
ute to daytime sleepiness in AD patients, sleepiness can
occur simply as a manifestation of AD. The disruption of the
sleep-wake rhythms manifests itself with large amounts of
daytime sleep and often an irregular sleep-wake rhythm dis-
order. As noted previously, there is degeneration of both the
suprachiasmatic nucleus (SCN) neurons and the pineal
neurons. Recently, a decrease in melatonin MT1 receptors in
the SCN has been demonstrated.5 This could be one reason
for the poor response to melatonin in AD. A large multi-
center trial of melatonin did not show an improvement in
elderly patients in group facilities.6 A recent study in AD
found that combined bright light and melatonin decreased
aggressive behavior and modestly improved sleep efficiency
and decreased nocturnal restlessness.7
OSA in AD OSA is common among patients with AD, and
several studies have suggested that continuous positive
airway pressure (CPAP) treatment of AD patients with OSA
can slow the deterioration of cognition and improve sleep
and mood.8
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 Chapter 31 Sleep and Neurologic Disorders 633

BOX 313 BOX 315

Sundowning Sleep Disturbance in Progressive Supranuclear
Definition: Nocturnal exacerbation of disruptive behavior or
Palsy
agitation in older patients Sleep disturbance present in most patients (>50%)
Factors Insomnia is the most common sleep disorder (more
severe than in AD or PD).
Early bedtime
RBD occurs (1330%)tends to start concomitantly
Use of sedatives
or soon after onset of PSP (unlike RBD in PD, which
Advanced cognitive impairment starts BEFORE manifestations of motor and cognitive
Associated medical conditions dysfunction).
Factors leading to insomnia
Immobility in bed.
BOX 314 Difficulty with transfer.
Alzheimers Disease Frequent nocturia.
AD = Alzheimers disease; PD = Parkinsons disease; PSP = progressive
Most common cause of dementia (60% of cases of supranuclear palsy; RBD = rapid eye movement sleep behavior disorder.
dementia)
Progressive intellectual deterioration in middle to late
adult life include hallucinations and dizziness (most common side
RBD much less common than in other causes of effect). Treatment with memantine can be combined with a
dementia cholinesterase inhibitor. Some studies have shown a benefit
Sundowning common from combined treatment.
Treatment is with cholinergic medications
RBD = rapid eye movement sleep behavior disorder. Medication-Induced Insomnia in AD Donepezil (Aricept) up to
10 mg has been associated with incident insomnia up to
18%. Morning dosing of donepezil is recommended to mini-
TABLE 312 mize insomnia. Whereas donepezil is a once-a-day medica-
Sleep Disturbance in Alzheimers Disease tion, rivastigmine is bid to tid and must be titrated up slowly.
EARLY AD LATE AD Rivastigmine and galantamine have more gastrointestinal
side effects than donepezil. The sleep of some AD patients
Disruption of sleep-wake Reduction in REM
may improve with evening doses of galantamine or rivastig-
rhythms
mine.10,11 Stahl and coworkers10 reviewed the results of
Increased nocturnal Increased REM latency double-blind studies of galantamine and found no higher
awakenings incidence of sleep side effects than with placebo. Rivastig-
Decreased stage N3 EDS and daytime napping mine improved sleep complaints in some studies.11,12 Whereas
not associated with OSA or cholinesterase inhibitors have been reported to improve
medications rapid eye movement sleep behavior disorder (RBD) in idio-
AD = Alzheimers disease; EDS = excessive daytime sleepiness; pathic RBD patients, rivastigmine has been reported to cause
OSA = obstructive sleep apnea; REM = rapid eye movement. RBD in patients with AD.13

Progressive Supranuclear Palsy

Treatment of AD Patients with AD have reduced cerebral pro-
duction of choline acetyl transferease, which leads to a
decrease in acetylcholine synthesis and impaired cortical
cholinergic function. Cholinergic medications (cholinester-
ase inhibitors) are used to treat AD and are beneficial.9
However, cholinergic medications can cause sleep distur-
bance. The cholinergic medications used to treat AD include
donepezil (Aricept), rivastigmine (Excelone), and galan-
tamine (Razadyne, formerly Reminyl). The dosage of the
medications is listed in Appendix 311. The cholinesterase
inhibitors tend to increase REM sleep.
Memantine (Namenda), an N-methyl-D-aspartate
(NMDA) receptor antagonist, is approved for treatment of
moderate to severe AD. It is thought to prevent excitotoxicity
from excessive glutamate actions at NMDA receptors that
can cause neuronal dysfunction. Memantines side effects
PSP is characterized by supranuclear extraocular gaze palsy.
Manifestations include a pseudobulbar palsy (upper neuron
lesion to corticobulbar tract with dysarthria and choking),
akinetic rigidity, ataxic gait and falling, limb and axial rigid-
ity, and frontal lobe type dementia. There is a lack of response
to dopaminergic medications.1,2
Sleep disturbance will be present in most patients (Box
315). Insomnia is the most common complaint (worse than
in AD or PD). Patients have an absence or a drastic reduc-
tion in REM sleep. Nocturia is a common problem. One
study comparing patients with AD and PSP found unsus-
pected OSA in approximately 50% of both groups.14,15 A high
and nearly equal percentage of both groups had REM sleep
without atonia. However, clinical RBD was less common in
PSP than in PD (7/20 vs. 13/20). If RBD is present in PSG,
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634 Chapter 31 Sleep and Neurologic Disorders
it presents concomitantly with other findings. In contrast,
RBD can occur many years before the onset of PD.
Physical Examination Impaired voluntary vertical gaze espe-
cially in downward direction is an early finding.
Epidemiology in PSP Patients with PSP have a mean age of 63
and the mean survival from symptoms is 9 years.
Histology Tau-positive neurofibrillary tangles are present in
multiple subcortical nuclei including the locus coeruleus.
There is relative preservation of the hippocampus and cortex.
Sleep in PSP PSP patients have severe sleep-maintenance
insomnia (worse than PD). Sleep complaints in PSP include
an increased sleep latency, increased arousals, increased
awakening frequency, decreased REM sleep, and increased
REM latency.14,15
Polysomnography in PSP Polysomnography (PSG) reveals
absence of vertical eye movements during REM sleep. Hori-
zontal movements are present but are slower.
Corticobasal Degeneration
CBD is a neurodegenerative disorder characterized by pro-
gressive asymmetrical rigidity, apraxia, and other findings
reflecting cortical and basal ganglia dysfunction.1,2 Tau-
positive astrocytic threads and oligodendral coiled bodies
are noted. Apraxia is characterized by loss of the ability to
execute or carry out learned purposeful movements, despite
having the desire and the physical ability to perform the
movements. It is a disorder of motor planning, which may
be acquired or developmental but may not be caused by
incoordination.
Frontotemporal Dementia
FTD is a type of cortical dementia resembling AD.1,2 It is
characterized by insidious onset, early loss of insight, social
decline, emotional blunting, relative preservation of percep-
tion and memory, perseverance, and echolalia. Computed
tomography (CT) or magnetic resonance imaging (MRI)
shows frontal or anterior temporal atrophy.
Parkinsonism Syndromes (PD, PD+)
The term parkinsonism is used to refer to a group of mani-
festations including tremor, rigidity, bradykinesia, and pos-
tural instability. Parkinsonism is found in both PD and
Parkinson Plus (PD+) disorders (Box 316).16,17 The PD+
disorders include those characterized by parkinsonism and
other manifestations. The PD+ disorders include PSP, DLBD,
and MSA. Of note, the brains of PD patients do have Lewy
bodies (LBs), but in DLBD, the distribution of LBs is more
dense and more diverse. DLBD patients have more promi-
nent dementia than noted in patients with PD. The dementia
BOX 316
Disorders Associated with Parkinsonism
Parkinsonism = tremor, rigidity, bradykinesia, and postural
instability
Disorders with parkinsonism
PDalso known as idiopathic parkinsonism
PD+disorders with parkinsonism + other
manifestations
PSP
CBD
DLBD
MSA
Medication side effects (dopamine blockers)
Wilsons disease (hereditary copper accumulation)
presents in younger patients with parkinsonism features,
diagnosis by slit lamp examination showing Kayser-
Fleischer rings
CBD = corticobasal degeneration; DLBD = diffuse Lewy body dementia;
MSA = multiple system atrophy; PD = Parkinsons disease; PSP = progressive
supranuclear palsy.
of DLBD also present much earlier in the course of the
disease than the dementia associated with PD. However,
there is overlap between PD and DLBD. The PD+ disorders
tend to progress more quickly than PD. The typically anti-
Parkinsons medications are either less effective or completely
ineffective in PD+ disorders. PD+ patients are also very
sensitive to dopamine blockers.
Differential Diagnosis of Parkinsonism
1. Essential tremorresponds to beta blocker, worse on
intention, improved with alcohol.
2. Wilsons diseasea disorder of hereditary copper accu-
mulation. The typical presentation is a young person who
has parkinsonian features. Diagnosis is by performing a
slit lamp examination for Kayser-Fleischer rings.
Parkinsons Disease
PD is also called primary parkinsonism or idiopathic PD. The
term idiopathic means no secondary systemic cause. The
etiology of PD is partially understood and, in this sense, is
not truly idiopathic. PD is a chronic neurodegenerative
disorder associated with a loss of dopaminergic neurons
(substantia nigra and other sites). It is characterized by bra-
dykinesia (slowing of physical movement), akinesia (loss of
physical movement), rigidity, resting tremor, postural insta-
bility, and a good response to levodopa (LD; Box 317).16,17
The disorder often starts unilaterally. Movements are slow
and reduced facial expressiveness is noted (masklike facies)
with infrequent blinking and a monotonous voice. Gait is
slow and shuffling with small steps. The tremor in PD is a
resting tremormaximal when limb is at rest and disappear-
ing with voluntary movement and sleep. Secondary symp-
toms may include cognitive dysfunction and subtle language
problems.
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BOX 317
Parkinsons Disease Manifestations
Resting tremor (pill rolling).
Gabellar reflex (sensitive but not specific)breakdown of
frontal lobe inhibition.
Masklike facies.
Small handwriting (micrographia).
Walking without arm swinging.
Flexed forward posture when walking with small shuffling
steps.
RBD in 2030%often precedes PD manifestations
sometimes by 10 years.
Insomnia in 50%.
OSA.
OSA = obstructive sleep apnea; PD = Parkinsons disease; RBD = rapid eye
movement sleep behavior disorder.
Nonmotor manifestations of PD include sleep disorders,
dementia, orthostatic hypotension, oily skin, and seborrheic
dermatitis. The sleep disorders in PD can occur secondary
to medication side effects but are also a primary manifesta-
tion of PD. PD patients have a sixfold increased risk of
dementia. Physical findings in PD include resting pill rolling
tremor, gabellar tap (tap of forehead elicits continued blink-
ing [a frontal lob sign]), and cogwheel rigidity (joint stiffness
and increased muscle tone). Imaging of the central nervous
system (MRI, CT scan) is typically normal. The neuropathol-
ogy of PD includes the presence of LBs. A major component
of LB is alpha synuclein. Secondary parkinsonism can occur
secondary to drugs such as dopamine blockers (phenothi-
azines and butyrophenones) or head trauma.
Differential Diagnosis of PD
1. Essential tremorResponds to beta blocker, worse on
intention, improved with alcohol.
2. PD+ disordersIf cognitive dysfunction occurs early in
the disease course of a patient with parkinsonism, DLBD
would be suspected. If early postural instability + supra-
nuclear gaze palsy is prominent early, the PSP should be
suspected. If autonomic dysfunction is prominent early
(erectile dysfunction or syncope), MSA should be
suspected.
3. CBDIf CT or MRI shows prominent asymmetry with
patchy changes and cortical deficits (apraxia) are promi-
nent, CBD should be suspected.
Treatment of PD A detailed discussion of the treatment of PD
is beyond the scope of this chapter. A very comprehensive
and useful discussion of PD is recommended.18 A number of
different medications have been used to treat PD (Table
313). The usual treatment of PD is with levodopa/carbidopa
(LD/CD). CD prevents peripheral metabolism of LD to
dopamine, thus reducing side effects and allowing for more
LD to reach the central nervous system. Patients may respond
to LD/CD but have a number of reported problems. On
times refers to periods of time when symptoms go away or
Chapter 31 Sleep and Neurologic Disorders 635
improve markedly. Off times refers to periods of time when
symptoms return. Wearing off time refers to times when
symptoms are under less control. Dyskinesias, manifested
by sudden jerky or uncontrolled movements of the limbs and
neck, are side effects of LD/CD treatment. Dystonias con-
sisting of abnormal posture or cramps of the extremities or
trunk can occur.
Dopamine agonists (DAs) are less likely to cause dyskine-
sia but have some dose-dependent side effects of their own.
In low doses, DAs tend to cause sleepiness or promote sleep.
Ropinirole or pramipexole have dopamine D2/D3 receptor
activity and can stimulate autoreceptors to decrease dopa-
mine release. In high doses, DAs can cause insomnia, fre-
quent awakenings, and a reduction in the amount of stage
N3. Another serious side effect of DA treatment of PD
patients is the often unpredictable sudden onset of severe
daytime sleepiness.
Catechol-O-methyl transferase (COMT) inhibitors have
also been used as adjunctive medications in PD. This enzyme
is involved in degrading neurotransmitters including dopa-
mine. The COMT inhibitors available include entacapone
(Comtan) and tolcapone (Tasmar). Entacapone is only
peripherally active, whereas tolcapone is active in both the
peripheral and the central nervous system. Tolcapone can be
hepatotoxic, whereas entacapone is not. These medications
can permit LD to last longer or maintain higher levels of
effectiveness.
Anticholinergic agents are typically used in younger
patients without cognitive impairment in whom tremor is
the major feature. The concept behind the use of these agents
is that PD has upset the cholinergic-dopaminergic balance
in the basal ganglia due to loss of dopaminergic neurons.
Anticholinergic drugs restore the balance. The anticholin-
ergic drugs do not work for other PD manifestations. LD
can also help tremor. The two anticholinergic drugs most
commonly used include trihexyphenidyl (Artane) and ben-
zotropine (Cogentin). Trihexyphenidyl is started at 0.5 to
1 mg bid and gradually increased to 2 mg tid as tolerated.
Benzotropine is used in doses of 0.5 to 2 mg bid.
Side effects of these medications including memory impair-
ment and hallucinations limit their use. The anticholinergic
side effects include dry mouth, constipation, and urinary
retention. Of note, LD improves tremor as well as rigidity
and can be used to treat tremor in patients not tolerating
anticholinergic medications.
Amantadine is an antiviral agent that can improve rigid-
ity, akinesia, or tremor in approximately two thirds of
patients. The mechanism of action is unknown. The usual
dose of amantadine is 100 to 200 mg one to three times daily.
The dose should be lower in patients with renal failure. The
starting dose of amantadine is 100 mg daily with slow
increases as tolerated. Side effects include confusion, hallu-
cinations, insomnia, and nightmares.
Selegiline (Deprenyl, Eldepryl), a selective monoamine
oxidase B (MAO-B) inhibitor, is approved for use in PD
patients as an adjunct to LD because it modestly increases
the percent of on time in advanced PD patients. When used
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TABLE 313
Medications Used to Treat Parkinsons Disease
Dopamine precursor Very effective for akinetic symptoms or tremor.
LD/CD Start 12 of 25/100 tid, titrate up to 25/100 tid.
10/100, 25/100, 25/100
SR LD/CD Poorly and slowly absorbed, 30% higher dose needed for same effect.
(25/100, 50/200 ER) Very low dose of SR can cause nausea owing to inadequate CD.
DAS Less likely than LD to cause dyskinesias.
Ropinirole (Requip) Can cause sudden episodes of severe sleepiness.
Pramipexole (Mirapex) Dopamine dysregulation syndrome.
Some recommend using DAs in younger patients as neuroprotective.
COMT Inhibitors These medications prolong the effect of LD and can allow a reduction in dose.
Tolcapone (Tasmar) COMT inhibition reduces the peripheral methylation of LD or dopamine, which increases
Entacapone (Comtan) the plasma half-life of LD; thus, prolongs action of LD.
Entacaponeperipheral inhibition of COMT.
Tolcaponeperipheral and central inhibition of COMT.
Tolcaponedeaths from hepatotoxicity.
Amantadine Antiviral.
May improve rigidity, akinesia, and tremor.
Monotherapy or combined with LD.
Trihexyphenidyl (Artane) For younger patients with predominant tremor.
Benzotropine (Cogentin) Side effects include cognitive impairment and typical anticholinergic side effects (dry
mouth, urinary retention, constipation).
MAOI (segiline) MAO-B inhibitor
Modest benefit; can be used with LD to reduce motor fluctuations.
CD = carbidopa; COMT = catechol-O-methyl transferase; DAs = dopamine agonists; ER = extended-release; LD = levodopa; MAO = monoamine oxidase;
MAOI = monoamine oxidase inhibitor; SR = sustained release.

alone at 5 mg bid, it is well tolerated. When used with LD, it
can increase dopaminergic side effects. Some clinicians use
selegiline at a lower dose in combination with LD to decrease
motor fluctuations. Other clinicians use selegiline as a puta-
tive neuroprotective therapy.
There is controversy about which dopaminergic medica-
tion is most appropriate for initiation of treatment of PD.
The most common approach is to start with LD/CD if symp-
toms are significant. LD/CD is particularly effective for
rigidity. However, patients taking LD/CD can develop dys-
kinesias. This tends to happen if patients have been on the
medication for years or if high doses are used. If a patient on
LD/CD develops dyskinesias, she or he can be switched to a
DA. Conversely, some clinics recommend starting a DA as
initial dopaminergic treatment. It is possible that DAs have
a neuroprotective effect not present with LD/CD.
Sleep-Related Manifestations of PD Patients with PD have a
number of sleep-related manifestations and disturbances
(Table 314).19,20 Treating the nocturnal manifestations of
PD can be challenging.
SLEEP DISTURBANCE DUE TO MOTOR MANIFESTATIONS Patients with PD
have motor symptoms including tremor that are worse
during wakefulness (Fig. 311) and usually decrease or are
abolished with sleep. The tremor often stops with the onset
of alpha activity during drowsiness even before the onset of
stage N1 or N2. Tremor is rare during stage N3. However, in
some patients, motor manifestations persist during sleep.
Examples of motor findings associated with sleep include
repeated eye blinking at onset of sleep, blepharospasm at the
onset of REM sleep, and prolonged tonic contractions of
limb extensor or flexor muscles during nonrapid eye move-
ment (NREM) sleep. Because of rigidity, patients with PD
have difficulty changing body position during the night.
Early morning akinesia and painful off dystonia can be prob-
lematic. LD/CD has a short duration of action. The DAs have
a longer duration of action and may be useful in patients
with motor manifestations during sleep.
DAYTIME SLEEPINESSIN PD Excessive daytime sleepiness (EDS)
not due to OSA or medications is a well-known phenome-
non in PD. Sleep attacks were once thought due to side
effects from DAs. Most recent studies suggest medications
used to treat PD may worsen EDS but that the underlying
disease process is the most common cause of EDS in PD.
Studies have reported 50% loss of hypocretin neurons in
patients with PD.21 Treatment of EDS not due to OSA in PD
patients includes modafinil, bupropion, and traditional stim-
ulants. Fatigue can also be a major complaint. The American
Academy of Sleep Medicine (AASM) practice parameters for
treatment of central hypersomnia22 state that modafinil may
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TABLE 314
Sleep Disturbance in Parkinsons Disease
PATHOPHYSIOLOGY MANIFESTATION TREATMENT
Changes in cholinergic and Impaired wake-sleep control Cautious use of sedating antidepressants
monoaminergic systems Decreased REM sleep and hypnotics
Bradykinesia and rigidity Decreased body shifts during sleep Sustained-release LD/CD or DAs
discomfort and increased awakenings
Impaired ability to use the bathroom
Tremor Arousals Sustained release CD/LD or DAs
Insomnia
Drug-induced dyskinesia Jerks, arousals Decrease evening LD/CD or DAs
Abnormal motor control of respiratory OSA (BMI often normal) CPAP
and upper airway muscles
RBD Disturbed REM sleep Clonazepam
Injury to self or bed partner Melatonin
RBD ?Dopamine agonists
May precede other findings by years
Prevalence 1530%
PLMS, RLS Arousals, difficult sleep onset Dopamine agonists
Depression and anxiety Insomnia Cautious use of hypnotics and
Difficulty with sleep onset antidepressants
Early AM awakening
Dementia Nocturnal confusional episodes Quetiapine
Aricept
BMI = body mass index; CD = carbidopa; CPAP = continuous positive airway pressure; DAs = dopamine agonists; LD = levodopa; OSA = obstructive sleep apnea;
PLMS = periodic limb movements during sleep; RBD = rapid eye movement sleep behavior disorder; REM = rapid eye movement; RLS = restless legs syndrome.
Adapted from Comella CL: Sleep disorders in Parkinsons disease. Curr Treat Options Neurol 2008;10:215221.

be an effective treatment of daytime sleepiness in PD.
However, the evidence from studies of the effects of modafinil
in PD is somewhat conflicting. A study by Ondo and col-
leagues23 found no significant improvement in the Epworth
Sleepiness Scale (ESS; subjective sleepiness). A study by Hogl
and associates24 found an improvement in the ESS but
no increase in the sleep latency on the maintenance of wake-
fulness test (MWT). An uncontrolled study by Nieves and
Lang25 found improvement in the ESS with modafinil in PD
patients. Another study investigated whether modafinil
would improve fatigue in PD. Using a double-blind, placebo-
controlled design, Lou and coworkers26 noted no improve-
ment in fatigue symptoms, no improvement in ESS, and
some improvement in finger tapping. In summary, even
though the evidence is less than totally convincing, a trial of
modafinil is indicated if daytime sleepiness is a significant
problem for a patient with PD. Of course, the possibility of
OSA should be eliminated. As noted previously, treatment
with DAs can be associated with sudden attacks of severe
daytime sleepiness. One case report found that the addition
of modafinil to DA therapy reduced the severity of this DA
side effect.27
can be the earliest manifestation, occurring many years
before other PD symptoms and signs. In general, treatment
options for RBD in PD are similar to those for idiopathic
RBD. DAs have been reported to be effective treatment of
RBD in some patients.
Nocturnal hallucinations can occur in PD and disturb
sleep. A recent study compared sleep between groups of PD
patients with and without visual hallucinations. Whereas
both groups slept poorly, the group with visual hallucina-
tions had much poorer sleep.28
Drug-induced psychosis is a major problem in PD. It can
occur in up to 22% and is a major cause of placing patients
in a chronic care facility. Treatments have included reducing
the dose of anti-Parkinsons medication, adding a neurolep-
tic drug, or discontinuing PD treatment for a period of time.
Low-dose clozapine was found effective even if anti-
Parkinsons medications were still taken and did not worsen
tremor. In this study, doses of 6.25 to 50 mg were used (far
lower than the 300900 mg used for schizophrenia). The
drug can cause leukopenia.29 Quetiapine has also been effec-
tive for drug-induced psychosis but can cause problems with
glucose control and oversedation.30

NOCTURNAL BEHAVIOR: RBD, NOCTURNAL HALLUCINATIONS, NOCTURNAL Dementia in PD A study found modest benefit from donepezil
PSYCHOSIS RBD occurs in 20% to 40% of patients with PD. It and the drug did not cause worsening of PD.31 Another study
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1234

E1-M2
E2-M2
F3-M2
F4-M1
1 sec
C3-M2
C4-M1
O1-M2
O2-M1
EMG1-EMG2
R Leg1 - R Leg2
L Leg1 - L Leg2

Nasal pressure

Chest

Abdomen

96 96 96 96 96 96 96 96 96 96 96 96 96 96 96
SpO2

ECG1-ECG2

11:33:27 PM 11:33:32 PM 11:33:37 PM 11:33:42 PM 11:33:47 PM 11:33:52 PM

FIGURE 311 A 30-second tracing during wakefulness in a patient with Parkinsons disease shows a classic 4-Hz tremor noted in the chin electromyogram (EMG).
RLeg1-RLeg2 and LLeg1-LLeg2 are the right and left anterior tibial EMG derivations. ECG = electrocardiogram; SpO2 = pulse oximetry.

has reported some benefit from memantine in patients with
PD with dementia or DLBD.32
Diffuse Lewy Body Dementia
DLBD is also known as dementia with Lewy bodies (DLB),
Lewy body dementia, or diffuse Lewy body disease. DLBD
is a type of dementia characterized anatomically by the
presence of Lewy bodies, clumps of alpha synuclein and
ubiquitine proteins in neurons. In this disorder, loss of cho-
linergic neurons results in cognitive dysfunction and loss
of dopamine neurons results in parkinsonism (Box 318).
If dementia occurs more than 1 year after other symptoms
in PD, the disorder is called PD with dementia. If dementia
occurs within the first year of parkinsonism, the diagnosis
is DLBD. DLBD tends to progress much more rapidly
than PD.
Manifestations of DLBD The major manifestations of DLBD33
include (1) fluctuating cognition with great variation in
attention and alertness from day to day and hour to hour, (2)
recurrent visual hallucination (75% of patients with DLBD),
(3) motor features of parkinsonism (tremor less common in
DLBD than in PD), (4) RBD (5075%), and (5) problems
with orthostasis, including repeated falls, syncope (fainting),
and transient loss of consciousness. The RBD can have an
onset years before the other manifestations of DLBD
(similar to PD).
VISUAL HALLUCINATIONS The most common reported hallucina-
tion is of people or animals. The patient may misinterpret
what he or she sees. For example, the patient may open a
drawer full of socks but see snakes.
SENSITIVITY TO DA BLOCKERS An important characteristic of
DLBD is exquisite sensitivity to dopamine blockers. When
given dopamine blockers, patients with DLBD can develop
life-threatening rigidity or malignant neuroleptic syndrome.
Anticholinergic drugs such as benadryl or hytrin can worsen
dementia.
DEMENTIA VARIANT A variant of DLB and RBD but without par-
kinsonism or hallucinations has been reported. This disorder
may be a variant of DLBD.34
Multiple System Atrophy
MSA is a neurodegenerative disorder characterized by a
combination of parkinsonism, dysautonomia, cerebellar dys-
function, and features of pyramidal tract dysfunction (Box
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 Chapter 31 Sleep and Neurologic Disorders 639

319).35 Some patients have more prominent dysfunction in
one category. MSA is sometimes divided into three separate
conditions (Table 315). These include (1) striatonigral
degeneration, (2) olivopontocerebellar degeneration, and (3)
progressive autonomic failure (Shy-Drager syndrome). A
BOX 318
Diffuse Lewy Body Dementia
Fluctuating cognition and alertness.
Visual hallucinations in 70%.
Orthostasis and frequent falls.
Motor manifestations of parkinsonism (rigidity, tremor
less common than in PD).
Onset of dementia within 1 year of symptoms of
parkinsonism.
RBD is very common (5080%).
Life-threatening rigidity with dopamine blockers.
PD = Parkinsons disease; RBD = rapid eye movement sleep behavior
disorder.
recent consensus conference35 recommended new MSA ter-
minology and the term Shy-Drager was not used in this
classification, although it is widely used in the literature.
Symptoms
1. Autonomic dysfunction (erectile dysfunction, bladder
controlurgency, incomplete emptying, constipation,
abnormal breathing during sleep, orthostatic
hypotension).
2. Parkinsonism = rigidity tremor, bradykinesia, and pos-
tural instability. The tremor of MSA is irregular and
usually not a pill rolling tremor as seen in PD.
3. Gait ataxia (poor coordination/unsteady walking) may be
a presenting symptom. Ataxia of speech (cerebellar dys-
arthria) is also common and manifested by slow and
slurred speech and sudden uncontrolled alterations in
loudness of voice.
Epidemiology of MSA The typical age of onset of MSA is 50
to 60 years. The disease course is fairly rapid with onset to
death in about 9 years. The disorder progresses more rapidly
than PD.

BOX 319 Diagnosis The second consensus conference on MSA defined

Manifestations of Multiple System Atrophy two categories of MSA based on the predominant symptoms
at the time of evaluation35:
Age of onset 5060 years.
Onset to death in 9 years. 1. MSA-PMSA with predominant parkinsonism (also
Not seen: hallucinations and dementia. called striatonigral degeneration, parkinsonian variant).
Orthostatic hypotension a major problem. 2. MSA-CMSA with predominant cerebellar features.
Variants MSA in which cerebellar features predominate is also
Striatonigral degenerationrigidity, bradykinesis. called sporadic olivopontocerebellar atrophy.
Olivopontocerebellar atrophyprominent ataxia,
postural instability. Pathology of MSA The pathology of MSA involves alpha
Shy-Dragerautonomic dysfunction. synuclein oligodendral inclusions in the brainstem, cerebel-
Stridorpoor prognostic sign, normal awake laryngeal lum, and spinal cord. Glial cytoplasmic inclusions (Papp-
examination does not exclude. Lantos bodies) appear in the brain centers involved with
Sleep disorders very common (>70%). control of movement, balance, and autonomic control
RBD very common (8095% of patients). centers.
OSA.
OSA = obstructive sleep apnea; RBD = rapid eye movement sleep behavior Vocal Cord Palsy and Stridor in MSA Stridor may occur in up
disorder. to 30% of patients with MSA. It can be much worse during

TABLE 315
Classifications of Multiple System Atrophy
1996 CONSESNUS 2007 CONSENSUS
CHARACTERISTICS CONFERENCE CONFERENCE
Striatonigral degeneration Predominantly Parkinsons type symptoms MSA-P MSA-P
Sporadic OPCA Progressive ataxia of gait, limbs, and MSA-C MSA-C
speech (cerebellar dysarthria)
Shy-Drager syndrome Characterized by parkinsonism + MSA-A No longer used
pronounced failure of the autonomic
nervous system
MSA = multiple system atrophy; OPCA = sporadic olivopontocerebellar atrophy.
From Gillman S, Wenning P, Low PA, et al: Second consensus statement of the diagnosis of multiple system atrophy. Neurology 2008;71:670676.
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640 Chapter 31 Sleep and Neurologic Disorders
sleep. A normal laryngeal examination during wakeful-
ness does not rule out the problem.36 The presence of
stridor is associated with a poor prognosis (compared with
MSA patients without stridor) and has traditionally been
managed by tracheostomy. Recently, CPAP has been used
to assist with stridor at night.36,37 Patients with MSA often
have OSA as well as worsening stridor during sleep. The
etiology of stridor is controversial but is likely due to over-
activity of the vocal cord adductors (close vocal cords) and
underactivity of vocal cord abductors (posterior cricoaryte-
noid muscles [PCAs]). A neuropathy of the recurrent laryn-
geal nerves that innervate the PCA muscles may be involved.
The syndrome of stridor in many patients is a dystonia rather
than vocal cord paralysis. In others, there is complete vocal
cord immobility. Sudden death has been reported in MSA
patients with stridor even though treated with tracheostomy
or CPAP.37,38
Central Apnea and Cheyne-Stokes Breathing Central apnea,
nocturnal hypoventilation, and Cheyne-Stokes breathing
(CSB) have been reported in MSA, especially in patients with
prominent autonomic features.39
Treatment of MSA The treatment of MSA is mostly support-
ive. There is usually no or only a short initial response to LD.
Patients with stridor can be treated with CPAP or tracheos-
tomy (although sudden death can still occur at night).
Other Neurodegenerative Disorders
Fatal Familial Insomnia
Fatal familial insomnia (FFI) is a familial autosomal domi-
nant prion disorder associated with the D178N mutation
and methionine-methionine genotype at codon 129 in the
prion protein gene on chromosome 20.40,41 Of note, the
D178N mutation and valine-valine genotype at codon 129
are associated with familial Creutzfeldt-Jakob disease (CJD).
Topography of Degeneration
Methionine-methionine genotype at codon 129 produces
dorsomedial and anteroventral thalamic dysfunction,
whereas the valine-valine genotype of CJD is associated with
more general cortical involvement.
FFI Manifestations
FFI manifestations include insomnia, dementia, ataxia, dys-
arthria, dysautonomia, hallucinations, and hypersomno-
lence. The duration from onset to death varies from a few
months to 4 years.
Diagnosis
The International Classification of Sleep Disorders, 2nd
edition (ICSD-2), diagnostic criteria for FFI are listed in Box
3110. The PSG in FFI reveals severe disruption of the sleep-
wake cycle, loss of sleep spindles, reduction in stage N3 and
stage R, as well as reduced sleep efficiency. REM sleep
without atonia can occur.
Positron Emission Tomography Scan
Positron emission tomography (PET) reveals nearly absent
or very low activity of the thalamus.
Summary
FFI should be considered in any patient with prominent
sleep-wake disturbance and dementia. Treatment is
supportive.
Sleep Disturbances in Stroke
Important points concerning stroke and sleep are listed in
Box 3111. SDB occurs in 50% to 70% of stroke patients
(defined by apnea-hypopnea index [AHI] > 10/hr).4246
Central sleep apnea including CSB can be noted, especially
soon after stroke, but tends to decrease with time. CSB in
some chronic stroke patients is associated with heart
failure.45,46 Other patients with stroke and central sleep apnea
have occult heart failure.47 OSA is the most common
BOX 3110
Fatal Familial InsomniaDiagnostic Criteria
A. Complaint of insomnia is initially present and becomes
progressively more severe.
B. Progressive autonomic hyperactivity with pyrexia,
hypersalivation, hyperhydrosis, cardiac and respiratory
dysfunction, tremor-like muscle activity.
C. Polysomnographic monitoring demonstrates
i. Loss of sleep spindles.
ii. Loss of slow wave sleep.
iii. Dissociated REM sleep.
D. The disorder is not better explained by another sleep
disorder, medical or neurologic disorder, mental
disorder, medication use, or substance use disorder.
OR
E. A missense GAC to AAC mutation at codon 17 of the
PRNP gene (d178N) co-segregating with the methionine
polymorphism at codon 129 of the PRNP on the
mutated allele is found (this mutation is absent in
sporadic fatal familial insomnia).
REM = rapid eye movement.
Adapted from International Classification of Sleep Disorders, 2nd ed.
Westchester, IL: American Academy of Sleep Medicine, 2005.
BOX 3111
Stroke and Sleep Apnea
OSA > CSA are common in patients after CVA.
If OSA is present, adequate treatment may improve
outcome.
CPAP treatment is often challenging, especially in
nonsleepy patients.
Incidence of stroke increased in men with mild to
moderate OSA.
CSA = central sleep apnea; CVA = cerebrovascular accident; OSA =
obstructive sleep apnea.
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 Chapter 31 Sleep and Neurologic Disorders 641

disorder following a cerebrovascular accident (CVA). OSA CLINICAL REVIEW QUESTIONS

also tends to improve with time, but a substantial number of
1. In which of the following dementias is RBD relatively
patients still have OSA at 2 to 3 months after stroke. However,
uncommon?
the presence of sleep apnea following a CVA raises questions
about the temporal relationship with stroke. Does brain A. PSP.
damage from CVA cause sleep apnea or did sleep apnea B. AD.
precede the stroke? If so, is the presence of sleep apnea an C. PD.
independent risk factor for the development of a CVA? The D. MSA.
Sleep Heart Health Study did show an increased risk of E. DLBD.
having a CVA (prevalence) if OSA is present.48 In a recently
published study, Redline and colleagues49 evaluated the Sleep 2. What neurodegenerative disorder is not an alpha
Heart Health data and found an increased risk for incident synucleinopathy?
ischemic stroke in men with mild to moderate OSA. In this
A. PSP.
study, data were adjusted for a number of confounders that
complicate the analysis including obesity. If there is a causal B. MSA.
role for OSA in stroke, what are the mechanisms? OSA could C. PD.
predispose a patient to atherosclerosis, hypertension, and D. DLBD.
early morning hemoconcentration. These factors would
increase the risk of stroke. During sleep apnea, there are 3. Which of these neurodegenerative disorders is frequently
increases in intracranial pressure (ICP)50 and decreases in associated with stridor?
cerebral blood flow.51 There is an increase in ICP with each A. PD.
apneic event and the rise tends to be correlated with the B. AD.
length of apnea. The increase in ICP is thought secondary to C. PSP.
increases in central venous pressure, systemic pressure, and
D. DLBD.
cerebral vasodilatation from rises in arterial partial pressure
of carbon dioxide (PaCO2) during events. Because cerebral E. MSA.
perfusion is proportional to the mean arterial pressure
(MAP)ICP, increases in ICP may reduce perfusion pres- 4. In which of the following disorders is sundowning a
sure even if MAP also rises. Studies of cerebral blood flow prominent feature?
velocity using Doppler monitoring have shown that flow A. AD.
velocity increases in early apnea, then has approximately a B. PD.
25% fall below baseline at end apnea.51 C. PSP.
There is some evidence that the presence of OSA in D. MSA.
patients who have suffered a CVA is a poor prognostic sign
regardless of whether OSA precedes or follows the CVA. 5. Which of the following is NOT a PD+ disorder?
Good and associates52 found that the Barthel index (a mul- A. PSP.
tifaced scale measuring mobility and activities of daily living
B. AD.
that is used to assess patients after stroke) was significantly
lower in patients with OSA and CVA compared with those C. MSA.
with no evidence of OSA after CVA. The presence of OSA D. DLB.
was determined at discharge and the Barthel index was lower
at 3 and 12 months in the OSA-CVA group. Martinez-Garcia 6. Which of the following is true about PD+ disorders com-
and coworkers53 found that CPAP treatment reduced mortal- pared with PD?
ity in patients found to have OSA following an ischemic A. There is a good response to LD.
stroke. This study suggests that physicians need to be more B. They have a slower downhill course than PD.
aggressive about ruling out OSA in patients with a recent C. They are very sensitive to dopamine blockers.
CVA. Unfortunately, CPAP adherence following CVA is D. Dementia is less common early.
often very suboptimal.
After stroke, other sleep-wake disorders may impair 7. Which of the following is true about patients with
recovery. Insomnia can occur but treatment should be cau- DLBD?
tious unless sleep apnea is excluded. Daytime sleepiness can
A. Dopamine blockers can cause life-threatening
occur even if sleep apnea is not present. Poststroke hyper-
rigidity.
somnia can be found after subcortical (caudate-putamen),
thalamomesencephalic, medial pontomedullary, and cortical B. Dementia starts about 2 years after rigidity and loss
strokes. In one study, up to 12% of patients developed new- of balance.
onset restless legs syndrome after stroke.54 Pontine-tegmental C. Visual hallucinations occur in 5%.
strokes can lead to RBD. D. They respond well to LD.
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642 Chapter 31 Sleep and Neurologic Disorders
Answers
1. B. RBD is uncommon in AD. RBD is very common
in PD, DLB, and MSA and tends to precede other neuro-
logic manifestations. RBD occurs in about 13% of PSP
patients and tends to start concomitantly with other
manifestations.
2. A. PSP is a tau disorder.
3. E. MSA is associated with stridor.
4. A. Sundowning is common in AD.
5. B. AD is not a PD+ disorder.
6. C. PD+ patients are very sensitive to dopamine blockers.
They have a more rapid course than those with PD, they
have minimal response to LD, and dementia can be
prominent early (DLBD).
7. A. Dopamine blockers can cause life-threatening rigid-
ity. Visual hallucinations are very commonup to 70%.
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 Appendix 31-1

Medications Used to Treat Alzheimers Disease

STARTING DOSE MAINTENANCE DOSE COMMENTS

Cholinesterase Inhibitors
Donepezil 5 mg po qd 10 mg qd Given in AM
Increase after 46 wk
Rivastigmine
Patch 4.6 mg/24 hr Increase to 9.5 mg/24 hr after 4 wk Rash, fewer side effects than pill
Pill 1.5 mg bid Increase in 1.5-mg increments Give with meals
bid every 24 wk until 6 mg bid
Galantamine Give with meals
Immediate release 4 mg bid Increase in 4-mg increments
monthly until 12 mg bid
Extended release 8 mg qd Increase in 8-mg increments
monthly until 24 mg daily
Neuroprotective
Memantine (Namendia) an NMDA receptor antagonist.
Can cause hallucinations and dizziness (most common side effect).
Can be used with cholinesterase inhibitors.

NMDA = N-methyl-d-aspartate.
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DaneshGroup.com
Glossary
A Confusional arousals A parasomnia characterized by confusion after
AASM American Academy of Sleep Medicine.
AASM scoring manual The AASM Manual for the Scoring of Sleep and
Associated Events. Iber C, Ancoli-Israel S, Chesson AL, Quan SF. West-
chester, IL, American Academy of Sleep Medicine, 2007.
Adaptive servoventilation A mode of positive airway pressure that varies
pressure support (IPAP-EPAP) to stabilize ventilation (or flow). ASV is
used for Cheyne-Stokes breathing or complex sleep apnea.
Advanced sleep phase syndrome (ASPS) Characterized by early sleep
onset and early wake time relative to societal (clock) norms in the
external world.
Alpha activity EEG activity of 813 Hz (see Alpha rhythm).
Alpha-delta sleep Prominent alpha activity occurring during stage N3
sleep.
Alpha rhythm 8- to 13-Hz activity recorded over the occipital region
during eye closure and attenuated with eye opening.
Alpha sleep Prominent alpha activity occurring during NREM sleep.
Apnea Absence of air flow (90% reduction) at the nose and mouth for 10
seconds or longer (using oronasal thermal sensor or CPAP flow).
Apnea-hypopnea index (AHI) The number of apneas and hypopneas per
hour of sleep.
Arousal In NREM sleep, an arousal is an abrupt shift in EEG frequency
including alpha, theta, and/or frequencies greater than 16 Hz (but not
spindles) that lasts at least 3 seconds with at least 10 seconds of stable
sleep preceding the change. Scoring of an arousal during REM sleep
requires a concurrent increase in the submental EMG that lasts at least
1 second.
ASDA American Sleep Disorders Association, now called the American
Academy of Sleep Medicine.
AutoCPAP (APAP) Autoadjusting or autotitrating CPAP units that deliver
the lowest required pressure at any time needed to maintain upper
airway patency.
Automatisms Involuntary or unconscious movements often described as
purposeless. They may mimic purposeful behaviors but are of no
benefit.
B sleep phase syndrome.
Beta activity EEG activity greater than 13 Hz.
Bilevel positive airway pressure (BPAP) Method of ventilation allowing
separately adjustable pressure levels in inspiration (inspiratory positive
airway pressure [IPAP]) and expiration (expiratory positive airway pres-
sure [EPAP]).
Biocalibration Recording of voluntary maneuvers during wakefulness at
the beginning of polysomnography to determine if the EEG, EOG, chin
and leg EMG, ECG, airflow, respiratory effort, and oximetry signals are
adequate. Electrodes of sensors are replaced or repositioned if necessary.
Biocalibrations are useful to determine if alpha rhythm is produced with
eye closure and to note the appearance of eyes open wakefulness.
Bruxism Clinching or grinding of the teeth (see Chapter 12 for scoring
rules).
C
C3, C4 Central EEG electrode on the right (left) side of the head.
Capnogram Tracing of exhaled PCO2 versus time. The plateau of the delec-
tion from each exhalation is the end-tidal PCO2 (an estimate of the
arterial PCO2).
Cataplexy Sudden loss of muscle tone (especially antigravity muscles) at
moments of high emotion (e.g., surprise, laughter, fear) with preserva-
tion of consciousness, characteristic of narcolepsy.
Central apnea Apnea associated with an absence of respiratory effort.
Cheyne-Stokes breathing Crescendo-decrescendo pattern of breathing
with central apneas or hypopneas at the nadir.
Chronic obstructive pulmonary disease (COPD) Chronic bronchitis,
emphysema, or a mixture.
Circadian rhythm sleep disorder (CRSD) Pattern of sleep disturbance due
to alterations of the circadian timing system or misalignment between
endogenous circadian rhythm and exogenous factors (clock time, soci-
etal demands) that affects timing or duration of sleep.
a spontaneous or forced arousal from sleep. Confusional arousals
tend to occur out of stage N3 sleep. In contrast to sleep terrors, there is
no autonomic hyperactivity, signs of fear, or blood-curdling scream.
Continuous positive airway pressure (CPAP) Maintenance of positive
airway pressure during inspiration and expiration.
Core body temperature minimum (CBTmin) Minimum core body tem-
perature occurs about 2 hours before habitual wake time, a marker of
circadian phase.
CPAP flow The flow signal from the positive airway pressure device uti-
lized in polysomnography (also known as PAP flow).
D
Delayed sleep phase syndrome (DSPS) Characterized by delayed sleep
onset and final wake-time relative to societal (clock) norms in the exter-
nal world.
Delta activity EEG activity at less than 4 Hz. In human sleep staging, slow
wave activity (SWA) is defined as a frequency 0.5 to 2 Hz with greater
than 75 V peak-to-peak amplitude (see Slow wave activity).
Derivation A set of two electrodes and the voltage difference between them
(e.g., C4-M1).
Desaturation Fall in arterial oxygen saturation from baseline, usually a 4%
or greater decrease.
Dim light melatonin onset (DLMO) The time that serum melatonin starts
to increase above daytime levels under dim light conditions. The DLMO
occurs about 2 to 3 hours before habitual bedtime or 7 hours before
CBTmin and is a marker of circadian timing (see Chapter 26).
Diurnal Pertaining to daytime.
E
E1, E2 Left and right electrode positions to recorded eye movements. The
recommended derivations are E1-M2 and E2-M2. E1 is 1 cm below the
left outer canthus and E2 is 1 cm above the right outer canthus (see
Chapter 1).
Early morning awakening Final awakening earlier than expected; charac-
teristic of depression, sleep-maintenance insomnia, or the advanced
Electroencephalogram (EEG) Recording of brain electrical activity.
Electromyogram (EMG) Recording of the electrical activity of a muscle.
In routine sleep monitoring, surface electrodes monitor EMG activity
in the chin area (three electrodes) and the right and left anterior tibialis
muscle (see Chapters 1 and 7).
Electro-oculogram (EOG) Recording of the electrical activity generated
during eye movements. In some texts the term is spelled without a
hyphen (electrooculogram).
EPAP Expiratory positive airway pressure.
Epoch A period of time usually corresponding to 30 seconds (one page of
recording at a paper speed of 10 mm/sec).
Epworth Sleepiness Scale (ESS) A score from 0 to 24 of the propensity to
fall asleep in eight normal situations (see Chapter 14). Normal is 10 or
less, and 24 is the maximal ESS score (the most sleepy).
F
F3, F4 Frontal electrodes over the right and left frontocentral portions of
the brain.
FEV1/FVC Ratio of the forced expiratory volume in 1 second to the forced
vital capacity. Reduced in obstructive airway disease. In this text, normal
is 0.70 and 90% of predicted.
Forced expiratory volume in 1 second (FEV1) The volume of air in
liters exhaled in the first 1 second of a maximal forced vital capacity
maneuver. In this text, normal is assumed to be 80% to 120% of
predicted.
Forced vital capacity (FVC) Volume of air in liters exhaled from maximal
inhalation (total lung capacity) to residual volume (maximal exhalation)
during a forced maneuver. In this text, normal is assumed to be 80% to
120% of predicted.
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648 Glossary
H Multiple sleep latency test (MSLT) Test to determine the mean sleep
Hypnagogic An event occurring on transition from wake to sleep.
Hypnagogic hallucination Vivid imagery at sleep onset; a feature of nar-
colepsy in which REM periods occur at sleep onset (see Chapter 24).
Hypnic jerk (sleep start) Brief total body jerk at sleep onset.
Hypnogram A graphical overview of the cyclic nature of sleep (see
Chapter 6).
Hypnopompic An event occurring on transition from sleep to
wakefulness.
Hypnopompic hallucination Vivid imagery at the transition from sleep to
wake (see Chapter 24).
Hypocretins Two peptides, Hcrt 1 and Hcrt 2 (also known as orexins A
and B), that are secreted by lateral posterior hypothalamic neurons.
Hypocretins project to many brain areas involved with the control of
sleep and wake. CSF hypocretin 1 is absent or very low in 90% to 95%
of patients with narcolepsy + cataplexy (see Chapters 7 and 24).
Hypopnea Reduction in air flow for 10 seconds or longer. Definitions vary
(see Chapter 9).
I criteria include an AHI of 5/hr or greater with symptoms or 15/hr with
ICSD-1, ICSD-2 International Classification of Sleep Disorders, 1st and
2nd editions.
Interictal Refers to transient focal or generalized discharges between
seizure events.
K P
K complex A well-delineated large-amplitude biphasic complex consisting
of a negative sharp wave (upward deflection) followed by a positive
component (downward) standing out from the background EEG, with
a total duration of 0.5 seconds or longer, usually maximal in the frontal
derivations.
K complex with arousal An arousal is associated with a K complex when
it commences no more than 1 second after termination of the K complex.
L Number of PLMs associated with arousal per hour of sleep.
Laser-assisted uvuloplasty (LAUP) Palatoplasty performed with a laser.
Left outer canthus (LOC) Outer corner of the left eye (formerly left eye
electrode placed slightly lateral and below the LOC).
Low-amplitude mixed frequency activity (LAMF) Low amplitude, pre-
dominantly 4 to 7 Hz activity.
Low chin EMG tone (REM level) Baseline chin EMG activity in the chin
derivation no higher than in any other sleep stage and usually the lowest
level of the entire recording (see Chapter 3).
M terized by foot flexion, big toe extension, and partial flexion at hip
M1, M2 Left and right mastoid electrodes (formerly A1 and A2). Frontal,
central, occipital, E1, and E2 electrodes are referred to the mastoid elec-
trodes (see Chapter 1).
Maintenance of wakefulness test (MWT) Test to determine the ability to
stay awake (see Chapter 14).
Major body movement (MBM) Movement and muscle artifact obscuring
the EEG for more than half of the epoch to the extent that the sleep stage
cannot be determined (see Chapter 3 for scoring rules for epochs with
a MBM).
Mean sleep latency (MSL) The mean of sleep latencies recorded during
naps over the course of a multiple sleep latency test or a maintenance
of wakefulness test.
Mixed apnea Apnea composed of an initial central part followed by an
obstructive component.
Montage The particular arrangement of a number of derivations that are
displayed simultaneously in a polysomnogram.
Movement arousal Defined in the R&K scoring manual as an increase in
the chin EMG accompanied by a change in pattern on any additional
channel. For EEG channels, qualifying changes include a decrease in
amplitude, paroxysmal high-voltage activity, or an increase in alpha
activity. Not used in the AASM scoring manual.
Movement time (MT) The total duration of epochs in which the sleep stage
is indeterminant owing to movement artifact in the EEG. Not used in
the AASM scoring manual (see Major body movement).
latency during daytime naps as an objective measure of daytime sleepi-
ness and the presence of REM sleep without 15 minutes of sleep onset
(sleep-onset REM periods). A diagnosis of narcolepsy requires 2 or
more SOREMPs (see Chapter 14).
N
Nasal pressure Used to detect airflow = K flow2, where K is a constant
(see Chapter 7).
Nonrapid eye movement (NREM) sleep Sleep stages N1, N2, N3.
O
O1, O2 Occipital EEG electrode on the left and right side of the head.
Obesity-hypoventilation syndrome (OHS) Daytime hypoventilation
(hypercapnia) not secondary to lung disease in an obese patient, usually
accompanied by severe obstructive sleep apnea.
Obstructive apnea Apnea with persistent respiratory effort.
Obstructive sleep apnea syndrome (OSAS) Syndrome characterized by
obstructive and mixed apnea and hypopneas. In adults, the diagnostic
or without symptoms.
Overlap syndrome Obstructive sleep apnea plus chronic obstructive
pulmonary disease (OSA + COPD).
Paradoxical insomnia The patient shows a consistent mismatch
between objective findings from PSG or actigraphy and subjective
sleep estimates derived from either sleep report or sleep diary (see
Chapter 25).
Parasomnia A condition associated with or occurring from sleep. Disor-
ders of arousal or partial arousal. Examples include sleepwalking, night
terrors, and REM sleep behavior disorder (see Chapter 28).
Periodic limb (leg) movementarousal index (PLM-arousal index)
Periodic limb movement disorder (PLMD) A disorder of sleep distur-
bance resulting in a sleep complaint (insomnia or, less often, excessive
daytime sleepiness) secondary to PLMS when other causes have been
ruled out. A diagnosis of RLS excluds a diagnosis of PLMD. A diagnosis
of PLMD requires a PLMS index greater than 5/hr in children or 15/hr
in adults. However, the normal range of the PLMS index is not well
defined and can be higher than 15/hr in normal elderly individuals (see
Chapter 23).
Periodic limb (leg) movement in sleep (PLMS) Leg movements charac-
and knee. To be considered part of a PLMS series (e.g., a PLM separately
by 5 and 90 seconds from onset to onset of consecutive movements),
a leg movement must be 0.5 to 10 seconds in duration and must occur
in a group (sequence) of four or more movements (see Chapters 12
and 23).
Periodic limb (leg) movement in sleep index (PLMS index or PLMSI)
Number of movements per hour of sleep.
Phase response curve (PRC) A curve characterizing the magnitude and
direction of the shift of the internal clock (circadian rhythm) induced
by light (or exogenous melatonin) as a function of the timing of light
relative to the baseline circadian rhythm (relative to the nadir in body
temperature).
Phasic REM sleep REM sleep in which rapid eye movements are present.
Polysomnography The detailed monitoring of sleep.
Popping artifact High-voltage artifact caused by temporary disconnection
of electrodes from the skin (see Chapter 4).
Psychophysiologic insomnia Conditioned sleep difficulty falling asleep in
bed at the desired time (the bedroom is a stimulus for arousal), height-
ened arousal and difficulty relaxing in bed, excessive focus on sleep, and
ability to sleep better away from home.
R
R&K The sleep staging criteria of Rechtschaffen and Kales, published in A
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Manual of Standardized Terminology Techniques and Scoring System

for Sleep Stages of Human Sleep. Los Angeles: UCLA, Brain Information
Service/Brain Research Institute, 1968.
Rapid eye movement density Number of eye movements per time in REM
sleep. Normally highest during the last REM peiods of the night.
Rapid eye movement sleep Stage R (see Chapters 3 and 5 for scoring
rules).
Rapid eye movement sleep behavior disorder (RBD) A parasomnia
occurring from REM sleep associated with REM without atonia and
dream enactment often with body movements and violent behavior (see
Chapter 28).
Rapid eye movements (REMs) Conjugate, irregular, sharply peaked eye
movements with an initial deflection lasting less than 500 msec. REMs
can be seen during eyes open wake or stage R.
Recording time; time in bed (TIB) Total time of sleep monitoring from
lights out to lights on.
REM latency Time from sleep onset to the start of stage R.
Respiratory arousal index (RAI) Arousals secondary to an apnea or
hypopnea, and in some sleep laboratoies, respiratory effortrelated
arousals.
Respiratory disturbance index (RDI) Definitions vary, RDI = AHI, RDI
= AHI + RERA index, RDI = apneas + hypopneas/monitoring time
(Centers for Medicare and Medicaid Services definition used for home
sleep testing). The RDI was not defined in the AASM scoring manual
OR in the ICSD-2.
Respiratory effortrelated arousal (RERA) An event characterized by an
arousal following a period of increased respiratory effort lasting 10
seconds or longer that does not qualify as an obstructive apnea or
hypopnea. Increased respiratory effort is detected by increased esopha-
geal pressure deflections or flattening of the nasal pressure signal (see
Chapter 8).
Respiratory inductance plethysmography (RIP) A method of detecting
chest and abdominal movement secondary to changes in the inductance
(a component of impedance) of bands around those regions. Used to
detect respiratory effort (see Chapters 7 and 8).
Restless legs syndrome (RLS) Syndrome marked by URGE: urge to move
legs, rest makes symptoms worse, gets better with movement (partial
temporary improvement), and worse in the evening. The urge to move
is often associated with uncomfortable sensation in the legs that can be
temporarily relieved by movement.
Right outer canthus (ROC) Right outer corner of the eye. The ROC elec-
trode is placed lateral to the ROC and slightly above the eye. The ROC
terminology and electrode placement has been replaced by the E2 elec-
trode (AASM scoring manual).
S usually with a duration less than 0.25 seconds superimposed on low
Saw-tooth waves Trains of sharply contoured or triangular, often serrated,
2- to 6-Hz waves maximal over the central regions, characteristically
seen during stage R, often before a burst of eye movements.
Sharp wave Duration 70 to 200 msec.
Sleep architecture The relative amounts of the different sleep stages com-
posing sleep and timing of sleep cycles (see Chapter 6).
Sleep efficiency Usually defined as total sleep time 100/time in bed.
Sleep hygiene Conditions and practices that promote continuous and
effective sleep.
Sleep latency Time from lights out (statistic of monitoring period) to the
first epoch of any stage of sleep.
Sleep-maintenance insomnia Difficulty maintaining sleep; frequent
awakenings.
Sleep-onset insomnia Difficulty falling asleep (usually sleep latency >
30 min).
Sleep paralysis Inability to move while still awake at sleep onset (hypnago-
gic) or at the end of a sleep period (hypnopompic). Sleep paralysis can
occur in normal individuals but is one of the symptoms of narcolepsy.
Episodes of sleep paralysis may be associated with hallucinations.
Sleep period time (SPT) Time from sleep onset until the final awakening.
Not used in the AASM scoring manual.
Sleep spindle EEG activity of 11 to 16 Hz (most commonly 1214 Hz)
with a duration of 0.5 second or greater, usually maximal in central
Glossary 649
derivations, characteristic of stage N2 (can also occur in stage N3) (see
Chapters 1 and 3).
Sleep stages Stage N1 (formerly stage 1), stage N2 (formerly stage 2), stage
N3 (formerly stage 3 + stage 4), and stage R (formerly stage REM) (see
Chapters 3 and 5 for scoring criteria).
Sleep starts (hypnic jerk) Brief whole body jerk at sleep onset.
Sleep state misperception (see Paradoxical insomnia).
Sleep terrors A parasomnia characterized by sudden awakening from
NREM sleep (usually stage N3 in children, but any stage of NREM sleep
in adults) with a cry or scream, confusion, and autonomic hyperactivity.
Sleepwalking (somnambulism) Characterized by a partial awakening
from NREM sleep (classically from stage N3 in children, but also N1
and N2 in adults) with complex movements including walking.
Slow rolling eye movement or slow eye movements (SEMs) Smooth,
undulating eye movements occurring during drowsy wakefulness and
stage N1 sleep.
Slow wave activity (SWA) Waves of frequency 0.5 to 2 Hz with a peak-to-
peak amplitude greater than 75 V. The amount of SWA determines
whether stage N2 or N3 is present. Score stage N3 when SWA is 20% or
higher.
Slow waves (delta waves) EEG waves with a frequency of 1 to 4 Hz (see
Slow wave activity).
SOREMPs Sleep-onset rapid eye movement periods. Stage R begins 15
minutes or less (clock time) after sleep onset.
Spike An EEG transient with a pointed peak and a duration of 20 to
70 msec.
Suprachiasmatic nucleus (SCN) Major circadian pacemaker in humans
(see Chapter 27).
Sweat artifact Slow undulations in EEG and EOG tracings secondary to
sweat (see Chapter 4).
T
Ten-twenty system An international standard for the placement of EEG
electrodes in which spacing of electrodes is 10% or 20% of the distance
between landmarks on the head (see Chapters 1 and 27).
Theta activity EEG activity at 4 to 7 Hz.
Three-minute rule An R&K scoring rule for determining how long stage
N2 could continue without a sleep spindle or K complex. Not used in
the AASM scoring manual.
Time in bed (TIB) Recording time total monitoring time, from lights out
to lights on.
Tonic REM sleep REM sleep in which rapid eye movements are absent.
Total sleep time (TST) Total minutes of stages N1, N2, N3, and R.
Transient muscle activity (TMA) Short irregular bursts of EMG activity
EMG tone during stage R. The activity may be seen in the chin or ante-
rior tibial EMG derivations. Formerly called phasic activity.
U
Upper airway resistance syndrome (UARS) Syndrome characterized by
daytime sleepiness secondary to frequent arousals related to increased
respiratory effort during periods of high upper airway resistance (nar-
rowing) without an abnormal amount of frank apnea or hypopnea. Most
authorities believe it is simply a mild form of OSA.
Uvulopalatopharyngoplasty (UPPP) An upper airway surgery for sleep
apnea and snoring. The uvula, a portion of the soft palate, and excess
pharyngeal tissues are removed.
V
Vertex sharp wave A negative sharp wave (upward deflection) with highest
amplitude in derivations containing electrodes near the vertex (e.g., Cz)
characteristic of stage N1 (typically near transition to stage N2). Accord-
ing to the AASM scoring manual, vertex sharp waves have a duration
less than 500 msec (usually sharp waves are defined as <200 msec).
W
Wake after sleep onset (WASO) Wake after sleep onset during the time in
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Note: Page numbers followed by f refer to figures; page numbers followed by t refer to tables; page numbers followed by b refer to boxes.
A Adult sleep staging (Continued)
Aberrant conduction, 167, 167f
Absence epilepsy, 563, 564f
Abstinent alcoholic, insomnia and, 496
Accelerated idioventricular rhythm, 164
Accelerated junctional rhythm, 164
Acid-base physiology, 148, 149f
Acromegaly, obstructive sleep apnea and, 241
Actigraphy, 205208, 206f
advanced sleep phase disorder and, 529
delayed sleep phase disorder and, 527528,
528f
hypersomnia and, 207
indications for, 206208, 207t
insomnia and, 207208, 487488, 487b, 488f
irregular sleep-wake rhythm and, 531, 531f
obstructive sleep apnea and, 207
Active sleep in newborns, 65, 69f
Acute mania, 604605
Adaptive servo-ventilation, 317, 317f, 318t, 334
Adenoidectomy, 253254, 363364, 364b, 364f
Adenosine, 9294, 99
Adjustment insomnia, 489490
differential diagnosis and, 490
key features of, 490, 490b
treatment and, 490
Adolescents
multiple sleep latency tests in, 225, 225t
sleep changes in, 86t
Adrenocorticotropic hormone (ACTH), 617,
617b
Adult normal sleep, 7981. See also Sleep
architecture
Adult respiratory events, 119134
apnea definition and, 121
apnea scoring rules, 122
chest-abdominal paradox, 128130, 130f
Cheyne-Stokes breathing rule, 132,
133f134f
event duration rules, 122123, 126f
false classification of apneas as central, 130,
131f
history of respiratory event definitions,
119121
hypopnea classification, 127128
hypopnea scoring rules, 122
hypoventilation in adults, 130132
hypoventilation rule, 131132
polysomongraphy reported parameters,
132134
recommended respiratory sensors, 121
relationship of arousal and respiratory event,
127
respiratory effort-related arousal detection,
124126
respiratory effort-related arousal rule,
124127
rules regarding, 121t
scoring apneas and hypopneas during wake,
127
Adult sleep staging
epochs with mixture of SSS/KCS and REMs,
4243, 43t
major body movements and, 4446
scoring by epochs, 2740
stage N1, 31
stage N2, 3135
stage N3, 3536
stage N2 vs. stage R rules, 4344
stage R, 3640
stage W (wake), 2730
transitions between definite stage N2 and
stage R, 4042, 40t, 41f
transitions between stage N1 and Stage R, 43
Advanced sleep phase disorder, 529530, 529b
core body temperature, dim light melatonin
onset, 529, 530t
diagnosis of, 529
epidemiology of, 529
morningness-eveningness questionnaire and,
529
pathophysiology of, 529
sleep logs and actigraphy and, 529, 530f
treatment of, 529530, 530t, 531b
Airflow limitation during sleep, 264, 264f
Airflow measurement techniques, 101107
Airway inflammation, asthma and, 422
Alcohol intake, obstructive sleep apnea and,
240
Alcoholism, insomnia and, 496
Aldosterone, 627628
Allergens, nocturnal asthma and, 423
Alpha-delta sleep, 5659, 626
Alpha intrusion, 5659
Alpha non-rapid eye movement sleep anomaly,
5659, 56t, 60f
Alpha rhythms, 3, 4t5t, 5f
Alpha sleep, 5659
Alternating leg muscle activation, 180181,
180f, 181t182t
Alternative EOG derivations, 7
Alveolar hypoventilation, 141
Alveolar plateau, 137
Alzheimers disease, 632633, 633b
medication-induced insomnia in, 633
medications used in, 645
obstructive apnea and, 632
sleep disturbances and, 632, 633t
treatment of, 633
Amantadine, 635
American Academy of Sleep Manual (AASM),
27, 28t, 85. See also Pediatric rules for
scoring sleep
electrocardiogram scoring rules, 163t
obstructive sleep apnea treatment
parameters, 303t
sensor recommendations, 102t
Amitriptyline, 505506, 505t
Amplifier filter settings for digital sleep
recordings, 20, 20t, 21f
Amplifier output scaling, 49, 50f
Amyotrophic lateral sclerosis, 142
Analog amplifiers, calibrations using, 49, 50f
Analog-to-digital (A/D) conversion, 16, 16f
Anticonvulsants, restless legs syndrome and,
441t, 443
Antidepressants
choice of, 599600, 599t600t
effects on sleep, 600, 601t602t
sedating, 505506, 505t
Antidromic entrainment, 535
Antiepileptic drugs effects on sleep, 563, 565t
Antipsychotics, sedating, 505506, 505t
Index
Anxiety disorders, 606610, 606t
generalized anxiety disorder, 608609, 608b
panic disorder, 606608, 607b
posttraumatic stress disorder, 609610, 609b
Apnea-hypopnea index (AHI), 102104, 105f,
105t, 119, 120t, 195196, 196t197t, 198f,
238
Apneas. See also Obstructive apnea
apneic threshold, 381382, 381f
definition of, 121
event duration criteria and, 123
false classifications of, 130, 131f
open or closed airways and, 315317, 316f
rules for children, 135136
scoring during wake, 127
scoring rules in adults, 122
types of, 122, 123f
Arginine vasopressin, 627628
Armodafinil, 307308, 463
Arousals
periodic limb movements and, 178, 179f
rules regarding, 4546, 45f, 45t
scoring of, 8586, 86f
Arrhythmias, obstructive sleep apnea and,
289290, 290f
Arterial blood gases, 141142, 145146, 146f
Arterial hypertension, obstructive sleep apnea
and, 286288, 287f, 287t
Arterial oxygen desaturations, 111112, 112f,
194f, 245247, 247b, 248f, 275276, 275b,
275f
Artifacts, 5156
60-cycle artifact, 54, 54t, 55f
ECG artifact, 5556, 56t, 57f
electrode popping, 5254, 52t, 53f
eye movement artifact, 56
ground artifact, 56
muscle artifact, 56, 58f
pulse artifact, 56, 58f
slow-frequency (sweat) artifact, 5455, 54t,
55f
snoring/respiratory chin EMG artifact, 56,
59f
Asthma. See Nocturnal asthma
Asynchronous sleep spindles, 74f
Asystole, 165166, 165f
Atherosclerosis, obstructive sleep apnea and,
291292, 291t
Atonia, 577
Atonic seizures, 556
Atrial fibrillation, 167, 167f, 170172, 171f
afib with a controlled ventricular rate,
170172
afib with a rapid ventricular response,
170172
ventricular pacer activity and, 173f
Atrial flutter, 170172, 171f
Atrial premature beats, 169f
Atrioventricular (AV) block, 166167
first-degree block, 166, 166f
second-degree block, 166, 166f
during sleep, 164168
third-degree block, 166, 167f
Atrioventricular dissociation, 167
Attended portable monitoring indications,
197
DaneshGroup.com
Aura, 556
651
652 Index
Autoadjusting positive airway pressure devices,
315, 316f
Autobilevel positive airway pressure, 317, 317f
Automatisms, 556
Automobile accidents, obstructive sleep apnea
and, 286
Autonomic arousals, 273274
Autotitration technique, 335, 335t
B bradycardia and AV block during sleep,
Bariatric surgery, 304
Basal forebrain, 96
Beck Depression Inventory, 485486
Behavioral insomnia of childhood, 493495,
494b
graduated extinction and, 495
key features of, 494
modified extinction and, 494495
treatment of, 494495, 495t
unmodified extinction and, 494
Behaviorally induced insufficient sleep
syndrome, 472, 472b
Bells phenomenon, 551, 551f552f
Benign epilepsy of childhood with
centrotemporal spikes, 562
Benzodiazepine receptor agonists, 500505,
500t, 600602
effects and side effects of, 482b, 501502,
501t
general considerations for, 502, 503t
medication choice and, 504505, 504t
restless legs syndrome and, 441t
Berlin questionnaire, 259
Beta blockers, insomnia and, 495496
Bilevel positive airway pressure
obstructive sleep apnea and, 325334
titration guidelines, 332t
Biocalibrations, 5051, 51f52f, 51t
Biofeedback, insomnia and, 498
Bipolar depression, 603, 604t, 606f
Bipolar disorders, 603605, 603b
acute mania, 604605
approved medications for, 605t
bipolar depression, 603, 604t, 605
genetics and, 604
maintenance treatments and, 605
mixed episodes, 605
sleep and, 603604, 604t
treatment of, 604605, 604b
Bipolar electroencephalogram recordings, 65,
66f
Bipolar longitudinal montages, 546548,
547f, 548t
Bipolar recording, 1417, 14t, 15f
Bland-Altman plot, 196197, 198f
Body-mass index, narcolepsy and, 457
Bradycardia, 164168
Bradytachycardia, 289
Brain areas important for sleep, 9196, 92t
activities of, 95t
brainstem regions, 9496
hypothalamic areas, 9194
Brainstem regions, 91, 93f, 9496
basal forebrain, 96
dopamine regions, 9495
reticular formation, 9596
Bronchodilator testing, 150
Bronchodilators, chronic obstructive
pulmonary disease and, 418419
Bruxism, 182184, 183f, 183t
Bundle branch block, 164
Bupropion, 599600, 601t
C idiopathic central sleep apnea and, 382383,
C-Flex, 320321, 320f
Calibrations, 4950
Cannula flow, 106f
Capnography, 113, 113f
Carbamazepine (Tegretol), 604605
Cardiac monitoring during polysomnography
aberrant conduction, 167
adverse events during polysomongraphy,
172
afib and atrial flutter, 170172
AV block, 166167
164168
conduction system and, 164
ECG recording, 160162
narrow-complex tachycardia, 168170
pacemakers and wide-complex QRS,
172173
premature beats, 167168
sinus pause/asystole, 165166
sinus rhythm and normative data for heart
rate, 162164
tachycardias during sleep, 168172
wide-complex tachycardia, 172
Cardiovascular disease, obstructive sleep apnea
and, 286288, 287t
Cataplexy, 457
isolated cataplexy in medical and neurologic
disorders, 469470
mechanisms of, 454
medications used to treat, 467t
preserved consciousness and, 457
treatment of, 465466, 466t
Catathrenia, 581583, 582b
diagnosis of, 582, 582f
differential diagnosis of, 582
epidemiology of, 581
polysomongraphy and, 581582
treatment of, 583
Catechol-O-methyl transferase inhibitors, 635
Central derivations, 554
Central hypopnea, 127128, 129f
Central sleep apnea, 122, 123f124f, 130, 136
apneic threshold and, 381382, 381f
with cardiac oscillations, 132f
Cheyne-Stokes breathing and, 385390
Chiaris malformation and, 396
complex sleep apnea, 390391
due to medication, 396397, 397b, 397f398f
hypercapnic, 392401
hypocapnic, 382385
idiopathic, 383385
loop gain and, 382, 382f383f
mechanisms inducing, 380t
multiple system atrophy and, 640
neural disorders causing hypoventilation
and, 396397
neuromuscular weakness and, 400401, 401f
normal physiologic changes and, 379380,
380t
pathophysiology of, 379382
primary sleep apnea of infancy, 397398,
399b
restrictive thoracic disorders and, 398400,
399f
syndrome classification, 377379, 377b378b
upper airway and posture effects and, 382
ventilatory control and, 380382
Cerebrovascular accidents
obstructive sleep apnea and, 292293
sleep disturbances and, 640641, 640b
Channel settings/montages, 2223, 23f
Chest-abdominal paradox, 128130, 130f
Cheyne-Stokes breathing, 132, 133f134f,
318319, 319f
383t, 384f
multiple system atrophy and, 640
Cheyne-Stokes breathing with central sleep
apnea, 385390
pathophysiology of, 386, 388f, 400t
polysomongraphy in, 385386, 386f387f
treatment of, 386390, 388b, 389f
Chiaris malformation, 396
Children. See also Pediatric obstructive sleep
apnea; Pediatric respiratory events;
Pediatric rules for scoring sleep; Sleep
architecture
multiple sleep latency tests in, 225, 225t
normal heart rate during wakefulness, 163t
normal sleep and, 85, 86t
sleep duration by age, 86, 87t
Chin EMG monitoring, 9, 9f10f, 37
Chronic bronchitis, 411t
Chronic obstructive pulmonary disease
(COPD), 142, 149, 411420
abnormal nocturnal gas exchange and, 412,
413f
bronchodilators and, 418419
functional residual capacity and, 413f
GOLD criteria for, 411t
hypnotics and, 419420
major mechanisms of, 412b
nocturnal noninvasive positive-pressure
ventilation and, 420
nocturnal oximetry in, 412f
non-rapid eye movement and, 414
nonapneic desaturation and, 415416, 415f
normal individuals and, 412413
overlap syndrome, 420
rapid eye movement and, 414415,
414f415f
respiration during sleep and, 416417, 417f,
417t
sleep quality in, 412420
sleep-related changes in respiration and,
413416, 414f
supplemental oxygen and, 417420, 418b,
418t
time of night and circadian variation of lung
function, 416
treatment of sleep-related hypoxemia in,
417420
Chronic partial sleep deprivation, 88, 88f, 89t
Chronotherapy, nocturnal asthma and, 424
Circadian clock genes, 524525, 525t
Circadian phase markers, 518520, 518b, 519f
Circadian rhythm shifting, 520524
phase-response curve for light, 521522,
522f
phase shifting by exogenous melatonin,
522524, 522t
phase shifting by light, 520521, 520b,
520f521f
Circadian rhythm sleep disorders (CRSD)
advanced sleep phase disorder, 529530
circadian phase markers, 518520, 518b
circadian physiology facts, 517b
circadian rhythm shifting, 520524
delayed sleep phase disorder, 526529
due to drug or substance, 540
due to medical conditions, 540
free-running type, 532537
general diagnostic criteria for, 525b
genomics of, 524525
irregular sleep-wake type, 530532
jet lag type, 533534
melatonin and, 516517
morningness-eveningness questionnaire and,
526
polysomnography and, 214
shift-work type, 537540
suprachiasmatic nucleus and sleep-wake
DaneshGroup.com
cycle, 517518

Circadian variation of lung function
asthma and, 421, 421f
chronic obstructive pulmonary disease and,
416
Claudication, restless legs syndrome and, 433
Clonic seizures, 556
Closed airway central apnea, 318319
Co-morbid insomnia, 499500, 506
Coffin-Lowry syndrome, 470
Cognitive therapy, insomnia and, 497
Comfort measures, positive airway pressure
and, 320322
Complex nocturnal visual hallucinations,
583584, 584b
Complex partial seizure, 556
Complex sleep apnea, 390391
incidence and natural history of, 390
pathophysiology of, 390
polysomnography and, 390, 391f
treatment of, 390391
Conduction system, cardiac, 164, 164f
Confusional arousals, 568569, 569b
diagnosis of, 569
differential diagnosis of, 569
polysomnographic findings during, 569, 569f
precipitating and predisposing factors, 569
prevalence of, 568
treatment of, 569
variants of, 569
Congestive heart failure, obstructive sleep
apnea and, 292
Continuation of REM sleep, 37, 37t, 38f
Continuous positive airway pressure,
obstructive sleep apnea and, 325334
Conversion disorder, hypersomnia associated
with, 474
Convulsive epilepsy, 556
Coronary artery disease, obstructive sleep
apnea and, 290291, 291f
Cortical arousals, obstructive sleep apnea and,
273275
Corticobasal degeneration, 634
Corticotropic axis, 617, 617b
Cortisol, 617, 617b
Cyclothymic disorder, 603, 603b
D 496t
Daytime sleepiness
common medications associated with, 473b
maintenance of wakefulness test and,
227232
multiple sleep latency test and, 221227
objective measures of, 221232
subjective measures of, 219221
DC signal calibration, 50, 50f
Dead space, breathing patterns and, 145, 145t
Definite REM sleep, 36, 37t
Delayed sleep phase disorder, 526529, 526b
epidemiology of, 526527
evaluation and treatment recommendations,
527t
pathophysiology of, 527
sleep logs and actigraphy and, 527528,
527f528f
treatment of, 528529, 528t
Dementias. See Neurodegenerative disorders
Dependence issues, insomnia and, 506
Depression. See also Major depressive disorder;
Major depressive episode
bipolar, 603, 604t
hypersomnia associated with, 474
with insomnia, 214
Desaturation, obstructive sleep apnea and,
276
Diabetes, obstructive sleep apnea and, 293
Differential amplifiers, 13, 14f
Diffuse Lewy body dementia, 638, 639b
dementia variant and, 638
dopamine blocker sensitivity and, 638
manifestations of, 638
visual hallucinations and, 638
Diffusing capacity for carbon dioxide, 151152,
151t
Digital gain adjustment, 2223, 23f
Digital polysomnography (PSG) systems,
2025, 22f. See also Polysomnography
channel settings/montages, 2223
grounds, 2425
impedance checking and, 23
montages for digital recording, 2122
referential display view and, 23
video-audio PSG, 24
Dissociative disorder not otherwise specified,
580
Dissociative fugue state, 580
Dissociative identity disorder, 580
Disturbed nocturnal sleep, narcolepsy and, 457
Divalproex (Depakote), 604605
Dominant posterior rhythm, 70, 71t, 551552,
552f
Dopamine agonists, 635
Dopamine dysregulation syndrome, 440442
Dopamine regions, 9495
Dopaminergic medications
periodic limb movement disorder and,
440443
restless legs syndrome and, 440443, 441t
side effects from, 442b
Dorsal raphe nucleus, 96
Dorsal reticular activating system, 95
Downward deflection, 7
Doxepin, 505506, 505t, 600
Drug or substance, parasomnia due to, 585
Drug or substance-related insomnia, 495, 496b
abstinent alcoholic and, 496
active alcoholism and, 496
alcohol effects and, 496
beta blockers and, 495496
causes of, 495496
epidemiology of, 495
key features and, 495
medications and substances known to cause,
treatment and, 496
Drug spindles, 59, 59t, 61f
Dual-chamber pacemakers, 173f
Duloxetine (Cymbalta), 599600
Dysfunctional Beliefs and Attitudes about Sleep
(DBAS) Questionnaire, 486
Dysfunctional Beliefs and Attitudes about Sleep
Worksheet, 513
Dysrhythmic disorder, 602603, 602b
E toward an electrode, 7
Eating disorders, sleep-related, 584585, 584b
Electrical quiescence, 66
Electro-oculographic derivations, 5t
Electro-oculographic monitoring, 79
Electrocardiogram artifact, 5556, 56t, 57f
Electrocardiographic recording during
polysomnography, 160162, 161f
Electrode nomenclature, 546f
Electrode popping artifact, 5254, 52t, 53f
Electrode positions using 10-20 system, 12,
2f3f
Electroencephalography (EEG)
age of onset and, 70t
electroencephalographic derivations, 23, 3t
electroencephalographic electrode
nomenclature, 2t
electroencephalographic electrode
placement, 17
Index 653
Electroencephalography (EEG) (Continued)
electroencephalographic patterns, 37
newborn infants and, 6566, 66t, 68f
patterns by conceptual age, 67f
Electroencephalography and nocturnal
epilepsy. See also Nocturnal epilepsy
bipolar monitoring and standard montages,
546548, 547f
electroencephalographic monitoring,
545546
eye movements and Bells phenomenon, 551,
551f552f
ictal activity, 554556, 555f
localization in referential and PSG montages,
549551, 550f
normal sleep waveforms in the 10-second
window, 551554
phase reversal and, 549, 550f
positive occipital sharp transients of sleep
and lambda and mu rhythms,
552554
posterior rhythm, 551552, 552f
waveform and seizure terminology, 548549,
549t
Emphysema, 411t
End of REM sleep, 37, 37t
Enuresis. See Sleep enuresis
Epileptiform activity, 548
Episodic nocturnal wanderings, 560561
Epworth Sleepiness Scale, 219221, 220f221f,
220t, 241, 242f, 242t, 485
Erectile dysfunction, obstructive sleep apnea
and, 293
Esophageal pressure deflections, 107108,
108f
Eszopiclone, 600602, 601f
Ethnicity, obstructive sleep apnea and, 240
Event duration rules, 122123, 126f
Excessive daytime sleepiness, 219, 460465,
461t. See also Daytime sleepiness;
Narcolepsy
choosing treatment for, 465
modafinil and armodafinil and, 463
obstructive sleep apnea and, 284286
selegiline and, 465
sodium oxylate and, 464465
stimulant medications and, 462463
Excessive fragmentary myoclonus, 181182,
182f, 182t
Exploding head syndrome, 583, 583b
Eye blinks, 8t, 72
Eye movement
artifacts and, 56
electrode positions and, 7, 7f
patterns and, 89, 8t, 9f
selective serotonin reuptake inhibitor
medications and, 59, 59t, 62f
Eyes-closed stage W, 27
Eyes-open stage W, 27
F
Familial nocturnal frontal lobe epilepsy,
561
Fatal familial insomnia, 640, 640b
Fee-running type CRSD, 532537, 533b
epidemiology of, 532533
pathophysiology of, 533
sleep logs and actigraphy and, 532f, 533
treatment of, 533, 533b, 533t
Fibromyalgia syndrome, 626627
manifestations of, 626
sleep and, 626
tender points and, 626f
treatment of, 626627, 626t
DaneshGroup.com
Firing rate, neuronal, 95, 96f
654 Index
First coast services durable medical area
contractor, 217218
accreditation and, 217
home sleep testing and, 217218
local carrier determinations and, 217
physical training/certification and, 217
First-night effect, 84
Flexible pressure, positive airway pressure and,
320321, 320f
Flip-flop model for rapid eye movement sleep,
98, 98f
Flow limitation arousals, 128f
Fluoxetine, 600602, 601f
Focal nocturnal epilepsy, 557558
Fractional saturation measurement, 110
Frontal derivations, electroencephalographic,
56, 6f
Frontotemporal dementia, 634
Functional residual capacity, 151
Functional saturation measurement, 109110,
110f
G 394395
GABA-benzodiazepine-chloride ionophore
complex, 500505
Gabapentin, 506
Gastric and intestinal function, 622623
Gastroesophageal reflux, 623625, 623b
nocturnal asthma and, 423424, 624625
nocturnal gastroesophageal reflux, 623624
normal gastroesophageal physiology and,
623
obstructive apnea and, 625
pH monitoring and, 623b, 624
sleep-related laryngospasm and, 625
treatment of, 625
Gender, obstructive sleep apnea and, 272273
General seizures, 556
Generalized anxiety disorder, 608609, 608b
differential diagnosis and, 608
sleep in, 608609
treatment of, 608609
Generalized epilepsy syndromes with nocturnal
seizures, 562563
absence epilepsy, 563
benign epilepsy of childhood with
centrotemporal spikes, 562
epilepsy with GTC seizures on awakening,
562
generalized epilepsy syndromes, 562
generalized seizures during or after sleep,
562563
juvenile myoclonic epilepsy, 562563
Lennox-Gastaut syndrome, 563
Genioglossus activity, 263269, 268f269f
Genioglossus advancement, 360361, 360f
Genomic of circadian rhythm sleep disorders,
524525, 524f, 525t
Ghrelin, 621622, 621b
Glottic pressure, 106f
Glucose tolerance, 622
Glutamate, 516
Gonadal axis, 621
Groaning. See Catathrenia
Ground artifact, 56
Grounds, polysomnography, 2425
Growth hormone, 615616, 616b
age-related changes in, 616, 617f
growth hormone releasing hormone effects,
616
sleep-related burst and, 616
twenty-four hour profile and, 615616, 616f
H ventilation patterns and, 382383, 383t, 384f
Hallucinations, 583584, 584b
Hamilton Depression Scale, 594
Head banging, 186f
Head trauma, recurrent hypersomnia and, 472
Heart rate, obstructive sleep apneas and, 245,
246f
Hemoglobin extinction curves, 104f, 110111,
111f, 144
Henderson-Hasselbalch equation, 149b
Herbst appliance, 350f
High-altitude periodic breathing, 391392
diagnostic criteria and, 392b
pathophysiology of, 392
treatment of, 392
High-frequency filters, 1920, 19f
High-voltage slow (HVS) pattern, 6566
Home sleep testing. See Portable monitoring
Homeostatic process, sleep-wake cycle and, 518
Hormone secretion control, 620621, 620t
Humidification, positive airway pressure
treatment and, 321322, 321f, 321t
Hyoid advancement, 360361, 361f
Hypercapnic central sleep apnea
central congenital hypoventilation syndrome,
mechanisms of, 393, 393f
patient evaluation with suspected
hypoventilation, 393394, 394b, 394f
Hypercapnic ventilatory response, 146148,
147f148f
Hypersomnia
actigraphy and, 207
as an undifferentiated somatoform disorder,
474
associated with major depressive episode,
474
associated with mental disorders, 472b473b,
473474
associated with seasonal affective disorder,
474
as a conversion disorder, 474
due to drug or substance, 471, 473b
due to medical conditions, 472473
idiopathic hypersomnia, 470474
nonorganic hypersomnia, 473474
not due to substance or known physiologic
condition, 473474
physiological (organic hypersomnia),
unspecified, 474
recurrent hypersomnia, 471473
Hypersomnias of central origin
cataplexy, 457
diagnostic testing for narcolepsy, 457460
narcolepsy due to medical condition,
468470
narcolepsy syndromes, 451457
treatment of narcolepsy, 460468
treatment parameters and, 466t
Hypnagogic foot tremor, 181, 181f, 181t182t
Hypnagogic hallucinations, 456, 467t, 583584,
584b
Hypnagogic hypersynchrony, 72, 73f
Hypnic jerks
parasomnias and, 586, 586b
restless legs syndrome and, 432
Hypnogram with rapid eye movement sleep,
276f
Hypnograms, 79, 80f
Hypnopompic hallucinations, 583584, 584b
Hypnotic-dependent patients, cognitive-
behavioral therapy and, 499500
Hypnotics, chronic obstructive pulmonary
disease and, 419420
Hypocapnic central sleep apnea
idiopathic CSA, 383385
ventilatory control in, 380382
Hypomanic episode, 596597, 596b597b
Hypopnea, 102104, 104f105f, 119, 120t
classification of, 127128
event duration criteria and, 123
idealized findings in, 129t
respiratory effort-related arousal and, 127
scoring during wake, 127
scoring rules in adults, 122
Hypopneic breathing, chronic obstructive
pulmonary disease and, 415416,
415f416f
Hypothalamic areas, 9194
lateral hypothalamus, 9192
tuberomammilary nucleus, 94
ventrolateral preoptic nucleus, 9294, 94f
Hypothyroidism, obstructive sleep apnea and,
240241
Hypoventilation, 141142, 142b
alveolar hyperventilation severity, 393394,
394f
central congenital hypoventilation syndrome,
394395
Chiaris malformation and, 396
evaluation of, 393394
muscular dystrophy and, 393394, 395f
neural disorders causing, 396397
neuromuscular diseases and, 394b, 401
neuromuscular weakness and, 400401
restrictive thoracic disorders and, 398400
rule for adults, 131132
rule for children, 137
sleep-related syndromes diagnostic criteria,
407408
syndromes, 377379, 378b
during wakefulness, 130132
Hypoxemia, 141142, 142t, 417420
I
Ictal activity, 554556, 555f
Ictal effects on sleep, 563
Idiopathic central sleep apnea, 383385
pathophysiology of, 384
polysomnography and, 384
treatment of, 384385, 385b
Idiopathic hypersomnia, 470474, 470b
with long sleep time, 470471, 470b471b
narcolepsy features vs., 456t
treatment of, 466t
without long sleep time, 471
Idiopathic insomnia, 492, 492b
Imagery rehearsal therapy, 579, 610
Impedance checking, digital polysomnography
and, 23
In-phase deflections, 7, 8f
Inadequate sleep hygiene, 493, 493b
Indeterminant sleep in newborns, 65
Infant sleep staging
bipolar electroencephalogram recording, 65,
66f
newborns, 6566
premature infant and infants younger than
48 weeks, 6568
premature infants, 66
scoring sleep in infants older than 40 weeks
and children, 7074
sleep architecture, 6768
term infants, 6667
Infants normal sleep, 85. See also Sleep
architecture
Insomnia
actigraphy and, 207208, 487488
adjustment insomnia (acute insomnia),
489490
behavioral insomnia of childhood,
493495
biofeedback and, 498
DaneshGroup.com
co-morbid insomnia, 499500, 506

Insomnia (Continued)
cognitive and behavioral treatments,
497500
detailed sleep history and, 483484
diagnostic criteria for, 482b
due to drug or substance, 495496
due to medical condition, 497
due to mental disorder, 492493
dysfunctional beliefs and attitudes about
sleep worksheet, 513
evaluation of, 483489
evidence levels concerning behavioral
techniques for, 499t
fatal familial insomnia, 640, 640b
GABA-BZ-chloride ionophore complex and,
500505
hypnotic-dependent patients and, 499500
idiopathic insomnia, 492
inadequate sleep hygiene and, 493
major characteristics of, 484t
major depressive disorder and, 598600
multicomponent therapy and, 498
paradoxical insomnia (sleep state
misperception), 491492
paradoxical intention and, 498
patients with dependence issues and, 506
pharmacologic treatment of, 500506
pharmacotherapy for co-morbid, 600602,
602t
physical examination and, 484485
physiologic findings in, 489
polysomnography and, 488489
prevalence of, 482
psychophysiologic insomnia, 490491
questionnaires and, 485486
ramelteon and, 505
relaxation therapy and, 498
risk factors and, 482
sedating antidepressants and antipsychotics
and, 505506
sleep logs and, 486
sleep restriction therapy and, 498
sleep-wake schedule and, 484
stimulus control therapy and, 498
subtypes of, 482483, 483b
treatment of, 497507
Inspiratory flow, 106f
Inspiratory positive airway pressure (IPAP),
314
Interface options, positive airway pressure
treatment, 322
Interictal activity, 548
Intestinal function, 622623
Intracranial pressure, obstructive sleep apnea
and, 292293
Iron-dopamine hypothesis, 434
Irregular sleep-wake rhythm, 530532, 531b
diagnosis of, 531
epidemiology of, 530
etiology of, 531
sleep logs and actigraphy and, 531, 531f
treatment of, 531532
J assessment of safety and, 231232
Jet lag type CRSD, 533534, 534b
antidromic entrainment and, 535
crossing more than eight time zones, 537
eastward flights, 535536, 535f
epidemiology of, 534
jet lag facts, 535t
pathophysiology of, 534
recommendations for, 536t537t
symptoms associated with, 535
treatment of, 535537
westward flights, 535f, 536537
Juvenile myoclonic epilepsy, 562563
K Mallampati score, 243244, 243f
K complex activity, 34, 4t5t, 4243, 43t
K complex and arousal, 34, 35f
Kleine-Levin syndrome, 471472
L Maximum expiratory pressure, 153
Lambda waves, 552554, 554f
Laryngospasm, gastroesophageal reflux and, 625
Laser-assisted uvulopalatoplasty, 300301
Laser-assisted uvuloplasty, 358359, 358f
Lateral dorsal tegmentum, 95
Lateral hypothalamus, 9192
Lateral positioning device, 306f
Leg cramps, restless legs syndrome and, 433
Leg movement event. See Limb movement
monitoring
Lennox-Gastaut syndrome, 563, 565f
Leptin, 621622, 621b
Lights on time, 79
Lights out time, 79
Limb movement monitoring
arousals and, 178
clinical significance and, 179180
criteria for, 176177, 177f
periodic limb movements in sleep, 178
periodic limb movements in wake, 178
respiratory events and, 177178
rules defining, 177t
suggested immobilization test, 179
techniques for, 175176
Limited-channel sleep testing. See Portable
monitoring
Lisdexamfetamine dimesylate, 464
Lithium, 604605
Localization in referential and PSG montages,
549551, 550f
Locus coeruleus, 96
Long QT, 160f
Loop gain, 270, 382, 382f383f
Low-amplitude mixed-frequency, 72
Low-frequency filters, 1719, 18f19f
Low-voltage irregular, 6566
Lung volume effects, obstructive sleep apnea
and, 269
Lung volume nomenclature, 150f
Lung volume testing, 151
M Mood disorders, 593605
Maintenance of wakefulness test, 227232
assessment of safety and, 231232
changes with treatment, 230231
definitions and test report, 230t
limitations of, 232, 232b
normative data for, 229, 230t
protocol, 229, 229t
relationship with multiple sleep latency test,
229232, 230t
sleep apnea and, 231t
specific indications for use of, 229
Major body movement (MBM), 3435, 35f,
4446
arousal rules and, 4546, 45f, 45t
scoring rules for, 44t
Major depressive disorder, 597602, 598b
antidepressants effects on sleep, 600, 601t
differential diagnosis of sleep disorder, 599
pharmacology for co-morbid insomnia,
600602, 602t
sleep and, 598600, 598b
treatment of, 599600, 599t
Major depressive episode, 594595, 594b
atypical subtype, 595
hypersomnia associated with, 474
impact on sleep, 595, 595b
melancholic subtype, 595
subtypes of, 595b
Index 655
Manic episode, 596, 596b
Mask pressures, 264, 266f
Maxillomandibular advancement, 302,
361362, 361b
Maximum inspiratory pressure, 153
Mean sleep latency, 224, 224b, 224f
Medical conditions
circadian rhythm sleep disorders and, 540,
540b
insomnia related, 497, 497b
parasomnia due to, 586
Medication-related central sleep apnea,
396397, 397b, 397f398f
Medications, rapid eye movement sleep and,
9899
Medications associated with nightmares, 579b
Melatonin
asthma and, 422423, 423f
circadian rhythm sleep disorders and,
516517, 519f
phase response curve and, 522523, 523f
phase shifting by, 522524, 522t
Melatonin receptor agonists, 503t
Menstrual-related hypersomnia, 472
Mental disorders
hypersomnia associated with, 473474
insomnia due to, 492493, 492b
Mesial temporal lobe epilepsy, 559
Methylphenidate, 462463
Mild obstructive sleep apnea, 300301
Mirtazapine, 505506, 505t, 599600,
601t602t
Mixed apnea, 122, 123f124f, 135136
Mixed chronic bronchitis and emphysema, 411t
Mixed hypopnea, 127128, 129f
Modafinil, 307308, 308f, 463, 464f
Moderate obstructive sleep apnea, 301302
Monitor resolution, signal recording and,
1617
Monoamine oxidase inhibitors (MAOIs), 601t
Montages, 23
channel settings/montages, 2223
digital recording and, 2122, 22t
Montgomery-Asberg Depression Rating Scale
(MADRS), 594
bipolar disorders, 603605, 603b
cyclothymic disorder, 603, 603b
depression questionnaires and, 594
dysrhythmic disorder, 602603, 602b
hypomanic episode, 596597, 596b597b
major depressive disorder, 597602, 598b
major depressive episode, 594595, 594b
manic episode, 596, 596b
mixed episodes, 596, 597b
severity rating scales and, 594
Morningness-eveningness questionnaire, 526,
526b, 529
Mu rhythms, 552554, 554t
Multiple sleep latency test, 86, 87f, 219227,
221b
changes with treatment, 230231
in children and adolescents, 225, 225t
clinical examples of, 225227, 226t
factors affecting mean sleep latency, 224,
224b, 224f
facts and, 223t
limitations of, 232, 232b
narcolepsy and, 225, 225t, 458459, 458t,
459f
protocol, 221223, 222b
relationship with maintenance of
DaneshGroup.com
wakefulness test, 229232, 230t
656 Index
Multiple sleep latency test (Continued)
report example, 227t
sleep apnea and, 231t
sleep-onset rapid eye movement periods and,
224, 224b
timetable and, 223t
two 30-second epochs of sleep during, 227f
values in normal populations and patients,
223224
Multiple system atrophy, 638640, 639b
central apnea and, 640
Cheyne-Stokes breathing, 640
classifications of, 639t
diagnosis of, 639
epidemiology of, 639
pathology of, 639
symptoms of, 639640
treatment of, 640
vocal cord palsy and stridor in, 639640
Muscle artifact, 56, 58f
Muscle forces, lung volumes and, 152153,
152f
Myoclonic seizures, 556
Myoclonus, propriospinal, 587, 587b
Myotonic dystrophy, 469
N Neuromuscular disorders, polysomnography
Narcolepsy. See also Cataplexy; Excessive
daytime sleepiness
cataplexy mechanisms and, 454
cataplexy treatment, 465466, 466t
children and, 467468
diagnostic criteria and important findings
for, 459460
diagnostic testing for, 457460
disturbed nocturnal sleep and, 457
epidemiology of, 453
excessive daytime sleepiness and, 455456,
460465
features of, 452t
future treatments for, 466467
genetics and, 453
Hcrt levels and, 459
Hcrt neurons and, 453454
history and, 452, 457458
HLA typing and, 453, 459
hypnagogic hallucinations and, 456
idiopathic hypersomnia vs., 456t
manifestations of, 455457
multiple sleep latency test and, 225, 225t,
458459
N-C group and, 454
narcolepsy facts, 453t
narcolepsy syndromes, 451457
narcolepsy with cataplexy (N+C), 454,
459460, 459b
narcolepsy without cataplexy (N-C), 460,
460b
pathophysiology of, 454
polysomnography and, 214, 458459
sleep paralysis and, 457
treatment of, 460468
Narcolepsy due to medical condition (NDMC),
468470, 468b
Coffin-Lowry syndrome, 470
genetic disorders and, 469
idiopathic hypersomnia, 470474, 470b
isolated cataplexy in medical and neurologic
disorders, 469470
Kleine-Levin syndrome, 471472
menstrual-related hypersomnia, 472
myotonic dystrophy, 469
Niemann-Pick type C disease, 469470
Norries disease, 470
rare genetic disorders and, 469470
recurrent hypersomnia, 471473
Narrow-complex tachycardias, 168170, 171f
Nasal congestion treatment, 306, 306t
Nasal masks, 322, 322f
Nasal obstruction, 358
Nasal-oral thermal sensor, 102, 104f, 106f
Nasal pressure monitoring, 119120
Nasal pressure sensors, 102, 104f
Nasal pressure techniques, 101107
Neocortical temporal lobe epilepsy, 559
Neurocognitive dysfunction, obstructive sleep
apnea and, 284286
Neurodegenerative disorders, 631641, 632b
Alzheimers disease, 632633
corticobasal degeneration, 634
dementias, 632
diffuse Lewy body dementia, 638, 639b
fatal familial insomnia, 640, 640b
frontotemporal dementia, 634
multiple system atrophy, 638640, 639b
Parkinsonian syndromes, 634, 634b
progressive supranuclear palsy, 633634,
633b
stroke, 640641, 640b
synucleopathies, 631632
Neuroleptic akathisia, restless legs syndrome
and, 432433
and, 213214
Neuromuscular weakness, central sleep apnea
and, 400401, 401f
Neuron activity, 91, 92f
Neuropathy, restless legs syndrome and, 432
Newborn sleep stages, 6566, 66t
Niemann-Pick type C disease, 469470
Night shift work, 538539, 538f539f, 539b
Night terrors. See Sleep terrors
Nightmare disorder, 578579, 579b
Nightmares, posttraumatic stress disorder and,
610
Nocturia, obstructive sleep apnea and, 293
Nocturnal asthma, 421425
airway inflammation and, 422
allergens in bedroom and, 423
characteristics of, 411t
chronotherapy and, 424
circadian alterations in lung function and,
421, 421f
diagnosis and treatment of, 422, 422b, 424
epidemiology and, 421422
etiology of, 422, 422b
factors worsening, 423424
gastroesophageal reflux and, 423424
gastrointestinal reflux and, 624625
manifestations of, 421b
melatonin and, 422423, 423f
obesity and, 424
treatment of, 424425, 424t, 425f
Nocturnal eating disorder, 586t. See also
Sleep-related eating disorder
Nocturnal epilepsy. See also
Electroencephalography and nocturnal
epilepsy; Generalized epilepsy syndromes
with nocturnal seizures
antiepileptic drugs and sleep, 563
bipolar monitoring and standard montages,
546548
classification of, 556557
electroencephalographic monitoring and,
545546
epilepsy syndromes associated with sleep,
558t
frontal lobe epilepsy, 559562, 561t
generalized epilepsy syndromes with
nocturnal seizures, 562563
ictal activity and, 554556
ictal effects on sleep, 563
Nocturnal epilepsy (Continued)
localization in referential and PSG montages,
549551
nocturnal frontal lobe epilepsy, 559562,
561t
nocturnal frontal lobe epilepsy syndromes,
560561
normal sleep waveforms in the 10-second
window, 551554
obstructive sleep apnea and, 563564
parasomnia vs. nocturnal frontal lobe
epilepsy, 561, 563t
phase reversal and, 549
seizure classifications, 556558
temporal lobe epilepsy, 559
timing of nocturnal seizures and sleep
effects, 558t
waveform and seizure terminology, 548549
Nocturnal hypoventilation, 141
Nocturnal leg cramps, restless legs syndrome
and, 433
Nocturnal paroxysmal dystonia, 587
Nocturnal wandering, 587
Non-rapid eye movement (NREM)
parasomnias, 568573, 573t. See also
Parasomnias
Non-rapid eye movement (NREM) sleep
chronic obstructive pulmonary disease and,
414
control of, 96, 96f
Nonapneic desaturation, chronic obstructive
pulmonary disease and, 415416,
415f416f
Nonconvulsive epilepsy, 556
Noninvasive positive pressure ventilation
(NPPV), 315, 330, 331f
chronic obstructive pulmonary disease and,
420
device reimbursement and, 338
goals and, 337
titration and treatment, 336337
titration protocol and, 337338, 337t
Nonorganic hypersomnia, 473474
Nonrespiratory physiology
corticotropic axis, 617
endocrine physiology and sleep, 615
fibromyalgia syndrome, 626627
gastric and intestinal function, 622623
gastroesophageal reflux and sleep, 623625
glucose tolerance, 622
gonadal axis, 621
growth hormone, 615616
leptin and ghrelin, 621622
obesity and sleep duration, 622
prolactin secretion, 619621
renin and aldosterone, 627628
thyroid axis, 617619
Nonrespiratory sleep disorders,
polysomnography and, 191t, 192
Nonselective serotonin reuptake inhibitors, 467t
Nonsupine rapid eye movement sleep, 195196,
196t197t
Norries disease, 470
Notch filters, 1920, 20f
O
Obesity
hypoventilation syndrome, 237238,
249250, 249b, 314
lung volume changes and, 152, 152f
nocturnal asthma and, 424
obstructive sleep apnea and, 239, 303305,
303f, 304t305t
sleep duration and, 622
Obstructive apnea, gastroesophageal reflux and,
DaneshGroup.com
625

Obstructive apnea/hypopnea event (OAHE),
119120
Obstructive hypopnea, 127128, 129f
Obstructive hypoventilation syndrome, 138
Obstructive lung disease
asthma, 421425
chronic obstructive pulmonary disease,
411420
obstructive ventilatory dysfunction, 409411
Obstructive sleep apnea, 122, 123f124f, 131f,
135. See also Oral appliances; Positive
airway pressure treatment
acromegaly and, 241
actigraphy and, 207
age and, 239
alcohol intake and, 240
apnea termination and arousal, 273275
arrhythmias and, 289290
arterial hypertension and, 286288
arterial oxygen desaturation and, 245247,
247b, 248f, 275276
atherosclerosis and, 291292
automobile accidents and, 286
cerebrovascular accidents and, 292293
childhood consequences of, 293294
common symptoms and manifestations of,
241t
congestive heart failure and, 292
coronary artery disease and, 290291
day-night pattern of sudden death and, 284,
284f
diabetes and, 293
diagnosis and, 241248
diagnostic criteria and, 238
epidemiology of, 238241
epilepsy and, 563564
Epworth Sleepiness Scale and, 219221, 220f,
220t
erectile dysfunction and, 293
ethnicity and, 240
evaluation recommendations for, 241t
excessive daytime sleepiness and, 284286
follow-up and outcomes assessment,
302303, 302t
gender and, 272273
genioglossus advancement and, 360361,
360f
heart rate and, 165f, 245, 246f
history and definitions and, 237238
hyoid advancement and, 360361, 361f
hypothyroidism and, 240241
international classification, 238b
key historical points and, 241242
laboratory testing and, 244
laser-assisted uvuloplasty and, 358359, 358f
lung volume effects, 269
male sex and, 239
Mallampati score and, 243244, 243f
maxillomandibular advancement and,
361362, 361b, 361f
mean arterial blood pressure and, 287288,
288f
medical treatment and, 303309, 303t
mild apnea treatment, 299, 301
modafinil, armodafinil, and stimulants and,
307308
moderate apnea treatment, 301302
mortality and, 282284, 285t
nasal obstruction and, 358
nasal patency and, 306
neurocognitive dysfunction and, 284286
nocturia and, 293
obesity and, 239
obesity hypoventilation syndrome, 249250
oral appliances and, 350357
overlap syndrome, 250251
Obstructive sleep apnea (Continued)
palatal implants and, 358
pathogenesis of upper airway obstruction,
263269
pathophysiology of, 282, 282f
patient education before treatment, 302, 302t
pediatric, 251254
pediatric medications and, 309
pediatric surgery and, 363364
persistent daytime sleepiness and, 307
physical examination and, 242244, 242b
polysomnography and, 190192, 246b
portable monitoring and, 205t, 247248
posture and positional treatment and,
305306
practice parameters for surgical treatment of,
373
prediction of presence of, 244, 244t
premenopausal status and, 239240
prevalence and progression of, 238239, 240f
primary (simple) snoring, 248249
pulmonary hypertension and, 288289
radiofrequency ablation and, 359
rapid eye movement sleep and, 244245,
245f
respiratory events and, 245247, 247t
risk factors and, 239241, 239t
severe apnea treatment, 302
smoking and, 240
snoring and, 300301
snoring variants and, 248251
stage R effects and, 270272
stepped surgical approach and, 363f
stroke and, 640641, 640b
supplemental oxygen and, 306307, 307f
surgical evaluation and, 357
surgical indications and, 357
surgical options and, 357362, 357b
surgical practice parameter
recommendations, 362b
surgical success rates and, 363, 363t
surgical treatments for, 357364
suspected sleep apnea and, 244247
sympathetic nerve activity and, 282, 283f
thrombosis and, 291292
tongue procedures and, 362
tracheostomy and, 357358
treatment categories and, 300, 301t
treatment selection and, 300302, 300t
upper airway resistance syndrome, 249
upper airway sensation and, 275
uvulopalatal flap and, 360
uvulopalatopharyngoplasty and, 359360,
359b, 359f
ventilatory control and, 270
weight loss and, 303305, 303f, 304t305t
Obstructive sleep apnea hypopnea syndrome
(OSAHS), 237238
Obstructive ventilatory dysfunction, 149,
409411, 410f, 411t
Opiate/narcotic-induced central sleep apnea,
396397, 397b, 397f398f
Opiates, restless legs syndrome and, 441t, 443
Opioids, restless legs syndrome and, 441t, 443
Opponent model of sleep, 518f
Opposite mastoid electrode, 23
Oral appliances, 350357
combination with other treatments, 357
comparison with continuos positive airway
pressure, 354t
devices, 352353
effectiveness of, 352, 354355
exclusions and contraindications and, 351
follow-up and, 356, 356b
local coverage determination and, 371
mechanisms of actions and, 351
Index 657
Oral appliances (Continued)
Medicaid and Medicare and, 356
patient evaluation and, 350351
practical parameters for, 369370
selected appliances, 354t
side effects and complications and, 356357,
356b
titration/adjustment of, 353
treatment adherence and, 353354
treatment guidelines and, 355356, 355b
Orexin (hypocretin) enzymes, 91, 93f
Organic hyperosmia, unspecified, 474
Orthognathia, 243f
Out-of-phase deflections, 7, 8f
Overlap syndrome, 250251, 314, 420, 420b,
421t
Oxygen. See Supplemental oxygen
Oxygen hemoglobin dissociation curve, 143,
143f
Oxygen transport and saturation, 142145
Oxyhemoglobin saturation curve, 109, 110f
P
P wave, 159
Pacemakers
dual-chamber, 173f
wide-complex QRS and, 172173
PaCO2 determinants, 145, 145t
PaCO2 during sleep, 112113
Painful legs-moving toes (PLMT) syndrome,
433
Palatal implants, 358
Panic attacks, 588, 606, 607b
Panic disorder, 606608
diagnosis criteria for, 607b
differential diagnosis and, 607608, 607b
sleep and, 607, 607b
treatment of, 608
Paradoxical insomnia (sleep state
misperception), 491492, 498
differential diagnosis and, 491492
incidence of, 491, 491b
key features of, 491
objective findings and, 491
treatment of, 492
Paralysis, sleep, 578, 578b
Parasomnias
classification of, 568b
common features associated with nocturnal
events, 588t
confusional arousals, 568569
differential diagnosis of, 587588, 587t
due to drug or substance, 585
due to medical condition, 586
exploding head syndrome, 583
hypnic jerks and, 586
nightmare disorder, 578579, 579b
NREM parasomnias, 568573
parasomnia overlap disorder, 577
polysomnography and, 214
propriospinal myoclonus and, 587
recurrent isolated sleep paralysis, 578
REM sleep behavior disorder, 574578
sleep enuresis, 580581
sleep-related dissociative disorders, 579586
sleep-related eating disorders, 584585
sleep-related groanings, 581583
sleep-related hallucinations, 583584
sleep talking and, 586
sleepwalking, 569572, 570b
unspecified, 585
usually associated with REM sleep, 574579
vs. nocturnal frontal lobe epilepsy, 561, 563t
Parkinsonian disease
differential diagnosis of, 635
DaneshGroup.com
treatment of, 635636
658 Index
Parkinsonian syndromes, 634, 634b
Parkinsons disease, 634638, 635b
daytime sleepiness in, 636637
dementia in, 637638
drug-induced psychosis and, 637
medications used in, 636t
nocturnal hallucinations and, 637
recurrent hypersomnia and, 472473
sleep disturbances due to motor
manifestations, 636
sleep-related manifestations of, 636637,
637t
Paroxysmal arousals, 560561
Patient Health Questionnaire (PHQ), 594, 613
Pavor nocturnus. See Sleep terrors
Pediatric narcolepsy, 467468
Pediatric obstructive sleep apnea, 251254
cardiovascular consequences of, 294
consequences of, 293294
diagnosis of, 252254
epidemiology of, 252
international classification and, 252b
medications for, 309
metabolic and inflammatory consequences
of, 294
neurobehavioral consequences and, 294
normative respiratory values and, 253t
obstructive hypoventilation and, 253f
rapid maxillary expansion and, 364
sequelae of, 293t
tonsillectomy and adenoidectomy and,
253254, 363364, 364b, 364f
Pediatric patients, positive airway pressure and,
326
Pediatric periodic breathing rule, 138, 138f
Pediatric respiratory events, 134139
ages which scoring rules should be used,
134
apnea rules, 135136
hypopnea rule, 136
hypoventilation rule for, 137
obstructive hypoventilation and, 137f, 138
pediatric respiratory rules, 135t
periodic breathing rule, 138, 138f
polysomongraphy reported parameters,
138139
recommended sensors and, 135
respiratory effort-related arousal rules,
136137
Pediatric restless legs syndrome, 437, 437b
Pediatric rules for scoring sleep (AASM),
7074. See also Children respiratory event
scoring
additional waveforms of wakefulness,
7072
ages for which rules apply, 70
arousal rules, 74
dominant posterior rhythm, 70
pediatric stage N1 waveforms, 72, 72t
pediatric stage W rules, 72, 72t
scoring sleep stage, 70
sleep stage terminology, 70
stage N1 rules, 72, 74t
stage N2 rules, 7274, 75f
stage N3 rules, 74, 75f76f, 75t
stage R, 74, 75t
Pedunculopontine tegmentum, 95
Periodic limb movement disorder (PLMD),
439440
diagnostic criteria and, 439b
dopaminergic medications and, 440443
nonpharmacologic treatments and, 440
objective findings and, 439440
polysomnography and, 214
prevalence and manifestations of, 439
treatment of, 440445
Periodic limb movements in sleep, 437439.
See also Limb movement monitoring
arousal index and, 438439
arousals and, 178, 179f, 438
benzodiazepine receptor agonists and,
443444, 444t
clinical significance of, 179180
common syndromes and disorders and, 439,
439t
comparisons of, 182t
diagnostic criteria and, 180t
differential diagnosis and, 438
index, 431432
narcolepsy and, 457
PLMSI and PSG findings and, 437438
Peripheral arterial tonometry, 200201, 204f
Persistent daytime sleepiness, obstructive sleep
apnea and, 307
PETCO2 measurement, 113115
Pharyngeal passive closing pressure, 264, 266f
Phase-response curve for light, 521522, 522f
Phase reversal, 549, 550f
Phase shifting by light, 520521, 520b,
520f521f
Philips-Respironics device, 318
Physiologic findings, primary insomnia and, 489
Piezoelectric (PE) sensors, 108
Pittsburgh Sleep Quality Index (PSQI), 485
Plasma renin activity, 627628, 627f
Plethysmograph, 101102, 103f
Pneumotachograph, 101, 103f105f, 105t
Polysomnography, 189192. See also Cardiac
monitoring during polysomnography;
Digital polysomnography systems
AASM practice parameters for, 213214
adult respiratory parameters and, 132134
adverse events during, 172
apnea-hypopnea index and, 196t
bruxism and, 183184
catathrenia and, 581582
children respiratory parameters and, 138139
circadian sleep disorders and, 214
circumstances not indicated for, 191t
combined with portable monitoring, 182f
complex sleep apnea and, 390, 391f
confusional arousals and, 569, 569f
CSB-CSA and, 385386, 386f387f
depression with insomnia and, 214
ECG recording during, 160162, 161f
historical elements to review based on, 193t
insomnia and, 488489, 489b
narcolepsy and, 214, 458459
neuromuscular disorders and, 213214
nightmare disorder and, 579
nonrespiratory sleep disorders and, 191t, 192
obstructive sleep apnea and, 246b
parasomnias and, 214
periodic limb movement disorder and, 214
positive airway pressure titration and, 190t,
191192
rapid eye movement sleep behavior disorder
and, 185187, 185t186t, 575, 576f
restless legs syndrome and, 214, 436, 437t
rhythmic movement disorders and, 184185
seizure disorders and, 214
sleep enuresis and, 581
sleep-related breathing disorders and,
190192, 190t
sleep-related eating disorders and, 585
sleep terrors and, 572573
sleepwalking and, 571, 571f
sleepy patient and, 192
special elements to note during
interpretation, 194t
Polyvinylidene fluoride thermal sensor,
101102, 104f
Portable monitoring, 192203
accuracy and, 194197
apnea-hypopnea index and, 196t
classification of, 195t
clinical guidelines for, 215216
clinical use of, 197199
developments in use of, 193194
device choice and, 204t
device types, 199201, 200f
history of recent developments in, 196t
indications for attended, 197
indications for unattended, 198199
integration into overall patient care, 202203
method of device setup and return, 204t
methodology for, 200t, 215216
obstructive sleep apnea and, 205t, 247248
patient selection for, 199
peripheral arterial tonometry, 200201
practical considerations and, 201202
recommended methodology and, 199
using polysomnography and, 203
Positional discomfort, restless leg syndrome
and, 432
Positional treatment, obstructive sleep apnea
and, 305306, 306f
Positive airway pressure adherence, 323325
acceptable levels of, 324, 324f
early adherence importance, 323
factors predicting, 323, 323t
hypnotics, alcohol, and CPAP, 324325
interventions to improve, 324, 324t
in large studies, 323
side effects interventions and, 325t
Positive airway pressure titration,
polysomnography and, 190t, 191192
Positive airway pressure treatment
adaptive servo-ventilation titration protocol,
334
additional monitoring for NPPV titration,
330, 331f
adherence and, 323325
alternative methods of starting, 334338
autotitration technique, 335, 335t
comfort measures and, 320322
CompSA and, 333334
CPAP/BPAP for obstructive sleep apnea,
325334
effectiveness and, 314
flexible pressure and, 320321
follow-up and, 335336
general titration considerations and, 326,
326t
humidification and, 321322
interfaces and, 322
local carrier determination and, 345346
mechanism of action and, 313314
Medicare criteria for reimbursement and, 347
modes of, 314319, 314t, 315f
monitoring during, 326330, 327t
NPPV titration and treatment, 336337
NPPV titration protocol, 337338, 337t
obstructive sleep apnea and, 205t
patient selection for alternative titrations,
335
pediatric considerations and, 326
practice parameters and, 343344
ramp option and, 320
reimbursement for NPPV devices and, 338
sample device download and, 336f
supplemental oxygen and, 332333, 332t
titration adequacy and, 334
titration protocol, 330332, 331t
treatment indications and, 322323
volume-targeted, 319320
Positive occipital sharp transients of sleep,
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552554, 554f

Posterior rhythm, 551552, 552f
Posterior slow waves (PSW) of youth, 7072,
71f
Postictal state, 556
Postmenopausal status, obstructive sleep apnea
and, 239240
Posttraumatic stress disorder, 609610, 609b
associated features, 609
differential diagnosis and, 610
nightmares in, 610
treatment of, 610
Posture, obstructive sleep apnea and, 305306,
305f
Premature beats, 167168, 168t, 169f
Premature infant sleep stages, 66
Primary sleep apnea of infancy, 397398, 399b
Primary (simple) snoring, 248249
Progressive supranuclear palsy, 633634, 633b
Prolactin secretion, 619621, 620b, 620f
Propriospinal myoclonus, 587, 587b
Prostaglandin D2, 9294
Prozac eyes, 59, 59t
Psychiatry and sleep. See Anxiety disorders;
Mood disorders
Psychophysiologic insomnia, 490491
incidence of, 490
key features of, 490, 490b
objective findings and, 490491
Pulmonary function patterns, 150b, 151t
Pulmonary hypertension, obstructive sleep
apnea and, 288289, 289f
Pulse artifact, 56, 58f
Pulse oximetry, 110112, 112f
Q parasomnia overlap disorder, 577
Q wave, 159
QRS complex, 159, 160f
QS wave, 159
QT duration, 159
QT interval, 159
Questionnaires, insomnia and, 485486, 485t
Quetiapine, 505506, 505t, 602
Quiet sleep in newborns, 65, 69f
R Renin activity, 627628, 627f
R wave, 159
Radiofrequency ablation, 359
Radiofrequency palatoplasty, 300301
Ramelteon, 505, 602
Ramp option, positive airway pressure and, 320
Rapid eye movement (REM) sleep. See also
Parasomnias; REM sleep behavior
disorder; Stage R
adenosine and, 99
arousal followed by LAMF EEG and SEMs,
3738, 39f
chronic obstructive pulmonary disease and,
414415, 414f415f
continuation of, 37, 37t, 38f
control of, 4243
definite, 36, 37t
end of, 37, 37t
epochs with mixture of, 4243, 43t
features of, 9699
first-night effect and, 84
flip-flop model for, 98, 98f
gender differences and, 84
increase in chin EMG activity and, 37
latency and, 8384, 84t
latency decrease with age, 82, 82f
MBM followed by LAMF EEG and SEMs,
3839, 39f
medications effects on, 9899
obstructive sleep apnea and, 244245, 245f
parasomnias usually associated with,
574579, 574b
Rapid eye movement (REM) sleep (Continued)
pattern definition, 8t
reciprocal interaction model, 9798, 97f
transition to stage W or N3, 37, 38f
without atonia, 577
Rapid maxillary expansion, 364, 365f
Reading eye movements, 8t
Rechtschaffen and Kales manual, 27, 28t, 85
Reciprocal interaction model of rapid eye
movement sleep, 9798, 97f
Recommended EOG derivations, 7, 8f
Recovery from sleep loss, 88
Recurrent hypersomnia, 471473, 471b
behaviorally induced insufficient sleep
syndrome, 472
head trauma and, 472
hypersomnia due to medical condition,
472473
Kleine-Levin syndrome, 471472
menstrual-related hypersomnia, 472
Parkinsons disease and, 472473
treatment, 466t
Recurrent isolated sleep paralysis, 578, 578b
Referential display view, digital
polysomnography and, 23, 24f
Referential montages, 546548
Referential recording, 1417, 14t, 15f
Relaxation therapy, insomnia and, 498
REM sleep behavior disorder, 185187,
185t186t, 457, 574578
classifications and causes of, 574575, 574b
diagnosis of, 575576
differential diagnosis of, 577
epidemiology of, 574
pathophysiology of, 574
polysomnography in, 575, 576f
pseudo-RBD, 575
REM sleep without atonia, 577
scoring rules for electromyogram activity,
575b
status dissociatus, 577
treatment of, 577578, 577b
variants of, 577
Resistance-capacitance (RC) circuits, 18
Respiration during rapid eye movement sleep,
379380, 380f
Respiration monitoring. See also Adult
respiratory events; Children respiratory
events
airflow and tidal volume measurement,
101107
PaCO2 during sleep, 112113
PETCO2, 113115
pulse oximetry, 110112, 112f
respiratory events in adults, 119134
SaO2 measurement, 109110, 110f
snoring sensors, 115, 115f
TcPCO2 monitoring, 113115
Respiratory disturbance index (RDI), 121, 238
Respiratory effort measurement, 107109, 108t
Respiratory effort-related arousal (RERA),
107108, 119120, 122, 124127, 126f,
128f, 136137
Respiratory events, obstructive sleep apnea
and, 245247, 247t
Respiratory impedance plethysmography,
108109
Respiratory inductance plethysmography,
105107, 107f
Respiratory muscle electromyogram, 109, 109f
Respiratory physiology
acid-base physiology, 148, 149f
arterial blood gases, 141142
maximum expiratory pressure, 153
Index 659
Respiratory physiology (Continued)
maximum inspiratory pressure, 153
muscle forces and, 152153, 152f
muscle strength and, 152
normal changes in ventilation during sleep,
145146, 146f
obesity and, 152, 152f
oxygen transport and saturation, 142145
PaCO2 determinants, 145, 145t
pulmonary function testing, 149152, 150f
ventilatory control tests, 146148, 147f148f
Respiratory-related evoked potentials (RREP),
274
Respiratory sensor recommendations in adults,
121
Respiratory volume dysfunction, 151
Restless legs syndrome, 430437
abnormal sensations in, 431b
anticonvulsant medications and, 443
augmentation and, 442443, 442b
causes of, 433, 433b
children and, 437, 437b
claudication and, 433
clinical features of, 434, 434b
differential diagnosis of, 432433, 432t, 433b
dopaminergic medications and, 440443
essential diagnostic criteria and, 431, 431b
familial patterns and genetics and, 434, 434t
hypnic jerks and, 432
medical evaluation in, 435436, 436b
medications used to treat, 441t
neuroleptic akathisia and, 432433
neuropathy and, 432
nocturnal leg cramps and, 433
nonpharmacologic treatments and, 440
onset and clinical course of, 435
opioids/opiates and, 443
painful legs-moving toes syndrome and, 433
pathophysiology of, 434
polysomnography and, 214, 436, 437t
positional discomfort and, 432
prevalence of, 434435, 435f
sedative hypnotics and, 443444
sleep disturbance associated with, 435
study group rating scale and, 436b
supportive clinical features and, 431432,
432b
treatment algorithm and, 444445, 445t
treatment of, 440445
Restrictive thoracic disorders, central sleep
apnea and, 398400, 399f
Restrictive ventilatory dysfunction, 149
Reticular activating system, 9596, 95f
Reticular formation, 9596
Reticular nucleus, 3
Retinohypothalamic tract, 516, 516f
Retrognathia, 243f
Rhinitis, 306, 306t
Rhythmic anterior theta, 72, 73f
Rhythmic masticatory muscle activity, 182
Rhythmic movement disorders, 184185
classification of, 184t
head banging and, 186f
polysomongraphy and, 184185, 184t
prevalence of, 184t
Rotating work shifts, 539
Roux-en-Y procedure, 304
RR interval, 159
S
S wave, 159
Sampling rate, 16, 16t
SaO2 measurement, 109110, 110f
Saw-tooth waves, 4t5t, 67
Scoring sleep in infants older than 40 weeks
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and children, 7074
660 Index
Seasonal affective disorder, hypersomnia
associated with, 474
Sedating antidepressants and antipsychotics,
insomnia and, 505506, 505t
Sedating antipsychotic medications, 602t
Sedative hypnotics, restless legs syndrome and,
443444
Seizure classification, 556558, 557b
Seizure disorders, polysomnography and, 214
Selective serotonin reuptake inhibitors (SSRIs),
59, 59t, 466, 599, 601t
Selegiline, 465, 635636
Sensor recommendations, 102t
Severe obstructive sleep apnea, 302
Severity criteria for pulmonary function
testing, 157
Sexual behavior, sleep-related, 571
Sharp waves, EEG patterns and, 3
Shift-work type CRSD, 537540, 537b
circadian markers and, 538
epidemiology of, 537
evaluation and treatment of, 538t, 539540
night shift work and, 538539, 538f539f, 539b
pathophysiology of, 537
risk factors and, 537
rotating shifts and, 539
sleep logs and diaries and, 538
Sickle hemoglobin, 143, 143f
Silenor, 600
Simple partial seizure, 556
Sinus arrhythmia, 162163, 162f
Sinus bradycardia, 162163
Sinus pauses, 165166, 165f
Sinus rhythm, heart rate data and, 162164
Sinus tachycardia, 162163
Sixty-cycle artifact, 54, 54t, 55f
Sixty-Hz filters, 1920, 20f
Sleep apnea, 231t
Sleep architecture
adult normal sleep, 7981
arousals, 8586, 86f
changes with aging, 8183, 81t
facts, 80t
infants and children, 85, 86t
parameters, 80t
REM latency alternations, 8384
scoring system comparisons and, 85
sleep fragmentation, 8688
sleep latency and REM latency, 82, 82f
stage N2, 82, 83f
stage N3, 8283, 84f
stage R, 83, 84f
TST and sleep efficiency, 82, 82f
WASO and stage N1, 82, 83f
Sleep deprivation
chronic partial, 88, 88f, 89t
selective, 8788
total, 87, 87f, 87t
Sleep efficiency, age-related changes, 82, 82f
Sleep enuresis, 580581, 580b
polysomongraphy in, 581
primary enuresis, 581
secondary enuresis, 581
treatment for, 581, 581b
Sleep fragmentation, 8688
chronic partial sleep deprivation, 88, 88f, 89t
recovery from sleep loss, 88
selective sleep deprivation, 8788
total sleep deprivation, 87, 87f, 87t
Sleep hygiene, 497
Sleep latency, 79, 82, 82f
Sleep logs, 486, 486f487f, 487t
advanced sleep phase disorder and, 529, 530f
delayed sleep phase disorder and, 527528,
527f
irregular sleep-wake rhythm and, 531
Sleep monitoring basics
electro-oculographic monitoring, 79
electroencephalographic electrode
placement, 17
Sleep monitoring technology
amplifier filter settings for digital sleep
recordings, 20, 20t
digital PSG system overview, 2025
filters (low-frequency, high-frequency, and
notch filters), 1720
referential and bipolar recording, 1417, 14t
Sleep-onset rapid eye movement sleep
(SOREM), 224, 224b, 458
Sleep paralysis, 457, 467t, 578, 578b
Sleep-related breathing disorders,
polysomnography and, 190192, 190t
Sleep-related dissociative disorders, 579580,
580b
Sleep-related eating disorders, 584585,
584b585b, 586t
Sleep-related hallucinations, 583584, 584b
Sleep-related hypoventilation, 137
Sleep-related laryngospasm, gastroesophageal
reflux and, 625
Sleep-related movement disorders, 176t
Sleep-related rhythmic movement disorder,
184185
Sleep-related sexual behavior (sex-somnia), 571
Sleep-related violence, 571
Sleep restriction therapy, insomnia and, 498,
498b
Sleep spindles, 3, 4t5t, 5f, 4243, 43t, 74f
Sleep stage nomenclature, 2t
Sleep terrors, 572573, 572b
diagnosis of, 573
epidemiology of, 573
facts on, 572b
polysomnographic findings associated with,
573
precipitating and predisposing factors, 573
treatment of, 573
Sleep-wake cycle, 516518, 517f. See also
Circadian rhythm sleep disorders
Sleep-wake regulation, 518t
Sleepwalking, 569572, 570b
diagnosis of, 571
differential diagnosis of, 571
epidemiology and familial pattern of, 570
facts on, 570b
familial, precipitating, and predisposing
factors, 570571
polysomnographic findings in, 571, 571f
predisposing factors for, 570b
sleep disorders and the law, 572, 572b
sleep-related sexual behavior, 571
sleep-related violence, 571
treatment of, 572
Slow eye movements, 8t
Slow-frequency (sweat) artifact, 5455, 54t, 55f
Slow heart rate during sleep, 164165, 165t
Slow wave activity, 36, 4t5t, 549
Smoking, obstructive sleep apnea and, 240
Snoring
obstructive sleep apnea and, 248251,
300301
polysomnography and, 190192
sensors, 115, 115f
Snoring/respiratory chin EMG artifact, 56, 59f
Sodium oxylate, 464465, 464f
Somatoform disorder, hypersomnia associated
with, 474
Somatostatin, 617619
Somnambulism. See Sleepwalking
Somniloquy, 586
Spike and wave complex, 548
Spikes, EEG patterns and, 3
Spirometry, 149150, 150f
ST interval, 159160
Stage N1, 29t, 31, 31f, 43
age-related changes and, 82, 83f
pediatric scoring rules, 72, 74t
pediatric waveforms, 72, 72t
Stage N2, 3135, 4344
age-related changes and, 82, 83f
effect of arousals and, 34
effect of major body movement and, 3435,
35f
pediatric scoring rules, 7274, 75f
rules for, 33t
start and continuation of, 3134, 32f, 34f
summary of scoring, 33t
Stage N3, 34t, 3536
age-related changes and, 8283, 84f
pediatric scoring rules, 74, 75f76f, 75t
Stage R, 3640, 36f, 4344
age-related changes and, 83, 84f
with arousal, 46f
arousal followed by LAMF EEG and SEMs,
3738, 39f
continuation of REM sleep, 37, 37t
definite REM sleep, 36, 37t
end of REM sleep, 37, 37t
increase in chin EMG activity and, 37
MBM followed by LAMF EEG and SEMs,
3839, 39f
obstructive sleep apnea and, 270272, 271f,
273f
pediatric scoring rules, 74, 75t
thirty-second epoch of, 46f
transient muscle activity during, 59, 59t,
62f
transition to stage W or N3, 37, 38f
Stage W (wake), 2730, 28f, 28t29t, 30f, 72,
72t
Stanford Sleepiness Scale, 219, 220t
Starling resistor, 264265, 266f
Status dissociatus, 577
Stimulant medications, excessive daytime
sleepiness and, 462463
Stimulus control therapy, insomnia and, 498
STOP-BANG scoring model, 261
Stridor, 639640
Stroke, sleep disturbances in, 640641, 640b
Subcortical arousals, 273274
Suggested Immobilization Test (SIT), 179
Sundowning, 633b
Supine rapid eye movement sleep, 195196,
196t197t
Supplemental motor area epilepsy, 561
Supplemental oxygen
chronic obstructive pulmonary disease and,
417420, 418b, 418t
obstructive sleep apnea and, 306307, 307f
positive airway pressure treatment and,
332333, 332t
Suprachiasmatic nucleus, sleep-wake cycle and,
516518, 517f
Synucleopathies, 631632
T
Tachycardia-bradycardia cycles, 164165
Tachycardias during sleep, 168172
Afib and atrial flutter, 170172
common tachycardias, 170t
narrow-complex tachycardias, 168170
wide-complex tachycardia, 172
TcPCO2 monitoring, 113115
Temazepam, 498499, 499f
Temporal lobe epilepsy, 559
10-20 electrode position, 546f
Term infants sleep stages, 6667
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Testosterone levels, morning, 621, 621f

Thermal devices, airflow monitoring and,
101102, 103f
Thirty-second epochs, 31, 32f, 42f
Thornton anterior positioner, 351f
Three-dB filters, 18f
Thrombosis, obstructive sleep apnea and,
291292, 291t
Thyroid axis, 617619, 619b
Thyroid hormone levels, 619
Thyroid-stimulating hormone secretion, 619,
619b
Thyrotropin-releasing hormone (TRH),
617619
Tidal volume, 105107, 145, 145t
Tidal volume measurement techniques,
101107
Time window for display, 17
Titration considerations, positive airway
pressure and, 326, 326t
Tongue procedures, 362
Tongue retaining device, 350f
Tongue sustaining device, 350f
Tonic-clonic seizures, 556
Tonic seizures, 556
Tonsillectomy, 363364, 364b, 364f
Tonsillectomy and adenoidectomy, 253254
Total recording time (TRT), 79
Total sleep time, age-related changes, 82,
82f
Trac alternant (TA), 6566, 68f
Trac discontinue (TD), 6566, 67f
Tracheostomy, 357358
Transient muscle activity during REM sleep,
59, 59t, 62f
Transitions between definite stage N2 and stage
R, 4042, 40t, 41f
Transverse bipolar montages, 546548, 547f,
549t
Trazodone, 505506, 505t, 600, 601t602t
Tricyclic antidepressants (TCAs)
cataplexy and, 465466, 467t
depression and, 599
effects on sleep, 601t602t
Tuberomammilary nucleus, 94
U Vocal cord palsy, 639640
U wave, 159
Unattended portable monitoring indications,
198199, 199t
Unclassified seizures, 556
Upper airway muscle activity, 263269
Upper airway patency, 263269, 263t
Upper airway sensation, obstructive sleep
apnea and, 275
Upper airway surgery, 302, 302t
Upper respiratory resistance syndrome,
249
Upstream resistance, 264
Upward deflection, EEG patterns and, 3
Uvulopalatal flap, 360
Index 661
Uvulopalatopharyngoplasty, 300301, 359360,
359b, 359f
V
Valproic acid (Depakene), 604605
Ventilation changes during sleep, 145146, 146f
Ventilatory control, obstructive sleep apnea
and, 270
Ventilatory control tests, 146148, 147f148f
Ventral reticular activating system, 96
Ventricular premature beats, 168, 169f
Ventrolateral preoptic nucleus, 9294, 94f
Vertex sharp waves, 4t5t, 67, 72
Video-audio polysomnography, 24
Violence, sleep-related, 571
Voltage differences, EEG patterns and, 3
Volume-targeted bilevel positive airway
pressure, 319320
W
Wake after sleep onset (WASO), 79, 82, 83f
Waveform examples, 162f
Weight loss, obstructive sleep apnea and,
303305, 303f, 304t305t
Wide-complex QRS, 172173
Wide-complex tachycardia, 160161, 172, 172f
Z
ZZsoma positional sleeper, 306f
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